Danio rerio (zebrafish) is an elective model organism for the study of vertebrate development because of its high degree of homology with human genes and organs, including bone. Zebrafish embryos, because of the optical clarity, small size, and fast development, can be easily used in large-scale mutagenesis experiments to isolate mutants with developmental skeletal defects and in high-throughput screenings to find new chemical compounds for the ability to revert the pathological phenotype. On the other hand, the adult zebrafish represents another powerful resource for pathogenic and therapeutic studies about adult human bone diseases. In fish, some characteristics such as bone turnover, reparation, and remodeling of the adult bone tissue cannot be found at the embryonic stage. Several pathological models have been established in adult zebrafish such as bone injury models, osteoporosis, and genetic diseases such as osteogenesis imperfecta. Given the growing interest for metabolic diseases and their complications, adult zebrafish models of type 2 diabetes and obesity have been recently generated and analyzed for bone complications using scales as model system. Interestingly, an osteoporosis-like phenotype has been found to be associated with metabolic alterations suggesting that bone complications share the same mechanisms in humans and fish. Embryo and adult represent powerful resources in rapid development to study bone physiology and pathology from different points of view. Danio rerio (zebrafish) is an elective model organism for the study of vertebrate development. This is due to the unique characteristics of the embryo such as large clutches (up to 250 embryos/week), small size, rapid external development, and transparency of the larval body. Such advantages encourage the use of live imaging and powerful genetic tools based on mutagenesis. Moreover, automated systems have been coupled with zebrafish embryo to create one of the most important in vivo methods for drug screening, drug discovery, and toxicity testing. The combination of these characteristics makes zebrafish an excellent animal model for developmental studies, basic biomedical research, drug development, and translational medicine studies [ studies .Many structures and functions are common in the vertebrates, from human to fish. Bone is a heterogeneous tissue composed by a mineral phase, hydroxyapatite, organic phase , and water.Danio rerio and Homo sapiens has hired zebrafish as animal model to study different aspects of skeletal physiology and pathology: bone metabolism, tissue turnover, and resorbing activity [Zebrafish embryo is a powerful model to study osteogenesis, since five days after the fertilization of eggs the first mineralized vertebrae are already present and they can be visualized using vital dyes specific for the mineralized matrix . The simactivity . Bone tiactivity , 5. In aactivity .In the last decade, several examples have been produced by the scientific literature concerning the introduction of zebrafish as model to study human bone diseases. In this review, we focused the attention on two different points of view in zebrafish skeletal studies: embryos and adult animals. Which resources and methods they offer to the medical research?in vivo methods for mutagenesis studies and drug discovery. The combination of such characteristics makes zebrafish an excellent animal model to search and study genes involved in skeletal development. When mutated, those genes can generate hard tissue dysfunctions similar to human diseases. Zebrafish embryo mutants for bone development are very helpful to perform drug development and translational medicine studies [The main characteristics of the embryo such as rapid external development and transparency of the body make this model elective in organogenesis studies. The use of live imaging for mineralized tissue guarantees a complete representation of larval skeleton. Moreover, large clutches, small size, and automated systems have contributed to the creation of one of the most important  studies .In the last years, morpholinos have become the elective techniques to quickly investigate the role of a specific gene in a particular developmental pathway, including skeletal system . SeveralRecently, two alternatives for generating genomic mutations have been recently implemented in zebrafish such as transcription activator-like effector nucleases (TALEN) and the Crispr/Cas9 system [Two large-scale “big genetic screens” searching for zebrafish embryo developmental mutants were carried out in Boston and Tubingen in the early 1990s. By a forward genetic approach, it is possible to understand the role of the mutated gene in normal development. From the big screens, more than 50 embryo mutants with defects in cartilage and bone development were identified . Among tOsteogenesis imperfecta, scoliosis, arterial calcification, and osteoarthritis are some examples of human bone disorders modeled in zebrafish embryos derived from the genetic screenings .weissherbst (weh (tp85c)) mutant  exhibited a defective iron transport with severe hypochromic anemia. After the analysis of bone and cartilage during development, weh (tp85c) mutant larvae exhibit defects in the vertebral mineralization and osteoblast-specific gene expression. These data suggest that iron deficiency anemia affects bone formation modulating BMP signaling pathway in zebrafish embryos [Iron overload is a risk factor for osteoporosis but the correlation between iron deficiency and bone metabolism is not clear. In zebrafish, the  embryos .enpp1 induces in human patients ectopic mineralization of soft tissues and arteries, increasing the risk of arteriosclerosis and cardiovascular diseases. Zebrafish enpp1 mutants exhibit as well ectopic calcifications in several soft tissues suggesting a similar role of the protein in the calcium metabolism [Recently, generalized arterial calcification of infancy (GACI) has been linked to ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) together with some cases of pseudoxanthoma elasticum (PXE). The mutation in the gene tabolism . The conThe type I collagenopathies are a group of connective tissue disorders caused by mutations in type I collagen gene. Various forms of osteogenesis imperfecta (OI) and the Ehlers–Danlos syndrome (EDS) are human bone diseases derived from these defects. Several zebrafish mutants in collagen genes have been used to dissect the bone structural regulation system and pathogenesis of bone fragility .de novo mutations. The severity of the disease phenotype depends on the specific genetic defect [bone morphogenetic protein 1 (bmp1) gene (c.808A>G and c.1297G>T). Both variants generate a hypofunctional protein BMP1 as demonstrated using zebrafish embryo knockdown and rescue experiments. Indeed, mutant BMP1 cDNAs did not rescue in the bmp1a mutant the fin ruffling, which is the phenotype due to a reduced C-propeptide cleavage and consequent defective assembly of collagen helix [Osteogenesis imperfecta (OI) is a heterogeneous group of diseases characterized by susceptibility to bone fractures. Most patients are defective in the pathway of type I collagen biosynthesis and tissue organization with autosomal-dominant or autosomal-recessive inheritance. Most cases of OI are inherited, although some cases are the result of c defect . Recentlen helix .Genes involved in the endoplasmic reticulum (ER) secretion pathways have been tested with success in zebrafish embryo as candidates for bone fragility in OI pathogenesis such as membrane bound transcription factor peptidase site 1 (MBTPS1)  and plasbulldog exhibited defects in protein export system from the cellular ER generating a syndromic form of osteogenesis imperfecta [Chihuahua mutant embryos that carry a G574D (p. G736D) substitution in the α1 chain of type I collagen, where the administration of chemical chaperones 4PBA and TUDCA ameliorated bone mineralization in larvae [In addition, Sec24d-deficient zebrafish mutant perfecta . The impn larvae .Idiopathic scoliosis is a form of congenital vertebral malformation affecting 2-3% of children in the world, and it is characterized by a curvature of the spine in the absence of structural defects of the vertebral body. The pathogenic mechanisms of idiopathic scoliosis remain poorly understood but new and more informative animal models of scoliosis may contribute to the clarification of the molecular basis of the disease. It has been demonstrated that morphological defects of the zebrafish notochord can produce congenital vertebral defects in the latter stages. Three different recessive mutations on collagen type VIII alpha1a (col8a1a) gene were found in zebrafish leviathan mutant. The reduction of the collagen production affects the normal development of the embryonic notochord and generates vertebral column malformations at the adult stage .scoliosis shows a spinal curvature without vertebral malformations. In scoliosis, the genome sequencing identified a nonsense mutation in kinesin family member 6 (kif6 (gw326)) gene [kif6 gene developed a scoliosis phenotype identical to scoliosis mutant, confirming that spine curvature is due to the loss of KIF6 function. Overall, these findings demonstrate the power of the zebrafish screening resource to identify new candidate genes for human idiopathic scoliosis.Recently, a forward mutagenesis screening has been performed in zebrafish to identify new genetic targets for idiopathic scoliosis. The zebrafish recessive mutant 6)) gene . A transptk7) mutant zebrafish develops scoliosis-like phenotype at late larval and early juvenile stage associated with spinal curvatures of variable severity and normal vertebral bodies. PTK7 is a receptor tyrosine kinase conserved from human to fish and implicated in Wnt, Semaphorin/Plexin, and vascular endothelial growth factor (VEGF) signal transduction. Interestingly, maternal-zygotic ptk7 (MZptk7) mutant embryos, characterized by complete loss of function, show the scoliosis-like phenotype very early during spine development underlining the importance of the maternal PTK7 in the initial stages of skeletal development. After this study, a novel mutation that disrupts PTK7 function has been discovered within a single scoliotic patient, consistent with zebrafish data about the dysregulation of Wnt pathway in disease pathogenesis [Still talking about mutants, zygotic protein tyrosine kinase 7  and ladybird homeobox 1 (LBX1) .The role in axial bone development of ubiquitously expressed human LBX1 was studied using both gain-of-function and loss-of-function approaches in zebrafish. Overexpression of human or zebrafish lbx1 gene in zebrafish embryo generates axial developmental defects including defects in body curvature which, in some cases, are conserved up to the juvenile stage .paired box 1 (Pax1), a gene originally associated with spinal development and emerged from studies on undulated mouse strain carrying a missense mutation in Pax1 [Xe1, together with another candidate, PEC7, has been tested with green fluorescent protein-Tol2 (GFP-Tol2) enhancer assays in zebrafish embryos. Both regions displayed functional enhancer activity in the developing spine, specifically corresponding to somitic muscles [Another genome-wide association study on independent female cohorts from the United States of America and Japan identified an enhancer region distal to  in Pax1 . Such re muscles .basonuclin-2 gene encoding one of the most evolutionarily conserved zinc finger transcription factors (BNC2), with 98% of protein homology between mouse and human. BNC2 is expressed in many human tissues, including epithelial and germ cells, and its overexpression produced spine curvature in developing zebrafish in a dose-dependent manner [Another extended genome-wide association study using independent Japanese and Chinese populations identified a susceptibility locus for idiopathic scoliosis on chromosome 9p22.2. The crucial polymorphisms were found in the intron 3 of t manner .Family with sequence similarity 20 member C (fam20c) is a gene encoding a secreted protein kinase (FAM20C), which binds calcium and phosphorylates substrates involved in bone mineralization processes like osteopontin [fam20c, located on human chromosome 7p22.3 [fam20b revealed that Fam20b has a role in cartilage matrix production and skeletal development, showing similar morphological alterations found in human RNS patients [Raine syndrome (RNS) is an autosomal recessive genetic disease associated with generalized osteosclerosis, intracerebral calcifications, and facial dysmorphism. eopontin . Raine se 7p22.3 . Zebrafipatients .CYP26B1 encodes a member of the cytochrome P450 superfamily which is upregulated during osteoblast differentiation and responsible for retinoic acid degradation, suggesting that a reduction in retinoic acid signaling is required for normal osteogenesis. In humans, clinical cases of craniosynostosis have shown important phenotypic similarities with two zebrafish cyp26b1 mutants, named dolphin (dol) and stocksteif (sst), in which can be observed deficiencies in cartilaginous structures, bone fusions, and hypermineralization in facial and axial bones [Craniosynostosis is a developmental defect of the skull with premature fusion of the cranial sutures . In humaal bones .transcription factor 12 (TCF12) or twist-related protein 1 (TWIST1) genes ablate the coronal suture, as observed in human and rodent studies. Interestingly, TALEN-mediated inactivation of homolog genes in zebrafish embryos generates specific loss of the coronal suture [In Saethre-Chotzen syndrome, mutations in l suture .Several genetic studies with next-generation sequencing confirmed that a genetic cause of craniosynostosis can be identified in one-quarter of cases. Among these, mutations in two genes, TCF12 and ERF, were found to be predominant, whereas other mutations in CDC45, SMO, and SMAD6 are suggested to be involved in the pathogenesis . These dptdss1, which encodes phosphatidylserine synthase 1 (PSS1). The expression of the mutant PTDSS1 RNA in zebrafish embryo caused several dose-dependent developmental defects in 6% to 40% of embryos. Craniofacial anomalies, trunk angulation, small or absent eyes, and abnormal cartilage were observed in the affected embryos [Lenz–Majewski syndrome (LMS) is a genetic disease characterized by mental retardation and generalized craniotubular hyperostosis. By using whole-exome sequencing, different missense mutations have been identified in the gene  embryos .Recently, a transpose-mediated transgenesis has been used to stably express wild-type and mutant forms of human PTDSS1 ubiquitously or specifically in chondrocytes, osteoblasts, or osteoclasts in zebrafish embryo to better evidence the bone phenotype .endothelin-1 (edn1) in both mouse and zebrafish resulted in loss of identity of neural crest cells of the first pharyngeal arch with consequent misdifferentiation of lower jaw structures into maxillary-like structures [Auriculocondylar syndrome (ACS) is a human birth defect syndrome showing alteration in ear and mandible development. It has been hypothesized that defects in signaling molecules associated with the endothelin signaling pathway could affect the ability of the neural crest cells to form most of the bone, cartilage, and connective tissue of the face. In fact, gene disruption experiments of ructures . Subsequructures , or Wdr6ructures .ATP-binding cassette subfamily C member 6 (abcc6) gene. ABCC6 is a membrane transporter involved in the ATP/AMP/pyrophosphate pathway. In fact, pyrophosphate regulates deposition of calcium and other minerals in the tissues. Patients with PXE show reduced levels of circulating vitamin K and calcified lesions in the skin, eyes, and blood vessels [abcc6a results in extensive hypermineralization of the axial skeleton [Pseudoxanthoma elasticum (PXE) is a mineralization disease related to a more severe vascular calcification syndrome called generalized arterial calcification of infancy (GACI). PXE is associated with mutations in the  vessels . The mutskeleton . Vitaminskeleton  underlinSeveral studies on human osteoarthritis (OA) have been addressed to the genetic component of the disease , 45. In in vivo [Histological analysis of the cartilage of OA patients indicated that the tissues possess the characteristics of an endochondral ossification process. For that reason, the best candidate genes for OA were those related to the endochondral ossification. In situ hybridization and transgenic reporter experiments have been made with some of zebrafish homologous genes: Mcf2l, Gdf5, PthrP/Pthlh, Col9a2, and Col10a1. The spatiotemporal expression revealed that the genes were dynamically expressed during zebrafish skeletal development whereas some of them (col2a1 and col10a1) were specifically associated with chondrocyte hypertrophy in vivo .More recently, it has been demonstrated, in zebrafish col11a2 mutants, that the protein is correctly produced but early degraded in forming joint cartilage. These changes in shape and structural properties affect joint function .ripk2) gene, RIPK2104Asp, has been expressed in zebrafish embryos resulting in the upregulation of OA-associated genes [κB pathway enhancing the inflammatory response, which increases the risk of OA.Zebrafish studies contributed also to the analysis of the role of inflammation in the pathogenesis of OA. In particular, a hyperactive variant of the receptor interacting protein kinase 2 , SMC3, SCC2/NIPBL, SMC1, RAD21/MCD1, and proteins involved in the cell-cell cross-talk and related to the cohesin family [Roberts syndrome (RBS) and Cornelia de Lange syndrome (CdLS) are rare genetic diseases with overlapping phenotype and associated, among others, with craniofacial and limb abnormalities. Mutations were found in genes coding for the establishment of sister chromatid cohesion n family .esco2 was found upregulated during fin regeneration, and the knockout embryo was defective for bone growth in regenerating fins, confirming the role of esco2 in skeletal morphogenesis and in the pathogenesis of cohesinopathies [The zebrafish regenerating fin model has been used to test the role of ESCO2 in skeletal development and disease. The gene opathies .Gba1 knockout has been produced in zebrafish embryo using morpholino techniques. The phenotype resulted in an increased reactive oxygen species production and defective canonical Wnt signaling which caused impaired osteoblast differentiation and reduced osteogenesis [Gaucher disease (GD) is a genetic disease caused by loss of lysosomal glucocerebrosidase (GBA1), responsible for multiorgan malformations and skeletal defects. Impairment of osteoblastic activity and enhanced macrophage-dependent bone resorption have been hypothesized as pathogenic mechanisms . In ordeogenesis .There is growing scientific literature affirming that a disequilibrium of the gut microbiota (dysbiosis) is associated with several human diseases such as allergy, asthma, metabolic, cardiovascular, and bone diseases . DiffereLactobacillus rhamnosus, a component of the human gut flora, has been administered chronically with the diet to zebrafish embryo. Interestingly, backbone centra of the treated larvae exhibited more extensive calcification than the untreated controls. In fact, L. rhamnosus stimulates the expression of genes involved in osteogenesis such as runt-related transcription factor 2 (runx2), Sp7 transcription factor (sp7), matrix Gla protein (mgp), and bone gamma-carboxyglutamate (gla) protein (bglap) and inhibits the expression of sclerostin (sost), a bone formation inhibitor [Some studies about the effects of microbiota on zebrafish bone metabolism have been recently presented. In particular, nhibitor .in vivo screenings. High-throughput automatized technologies and zebrafish embryo can generate, together, a powerful resource for drug screening, target identification, pharmacology, and toxicology [The zebrafish has become an elective model for the phenotype-based drug discovery. Similarities and differences between human and zebrafish biology drove the use of zebrafish as a resource for xicology .in vivo screening using larval zebrafish has been developed to facilitate the identification of compounds with effects on osteogenesis. In these experiments, vitamin D3 analogs (VD) and intermittent administration of parathyroid hormone (PTH) have been used as positive control molecules. The live staining of mineralized tissues during skeletal development revealed that VD and PTH possess the same anabolic effect highlighted in humans. Such result underlined the metabolic similarity of the bone tissue between humans and fish and proposes in vivo screening as a powerful method to isolate new anabolic compound for human bone-loss diseases [In the past, high-throughput diseases .Recently, an automatized high-throughput optical projection tomography screening has been applied to developing zebrafish embryos to test several classes of teratogens for their effects on cartilage formation . TomograZebrafish embryo models recapitulating human bone diseases  can be used to screen for a compound able to rescue the pathological phenotype. This method facilitates the identification of novel compounds useful for further drug development.After hepatotoxicity, immunotoxicity, neurotoxicity, and/or reproductive toxicity studies, environmental toxicology has hired zebrafish embryo to screen pollutants affecting skeletal tissues (osteotoxicity) by acute or chronic exposure to different environmental insults .Col2a1aBAC:mCherry)hu5900 [1.7col2a1a:mCherry-caax) [The transparency of the zebrafish larva leads itself to the use of noninvasive staining methods which include vital dyes and transgenic fluorescent animals. Live staining of embryos with fluorescent dye such as calcein  and alizy)hu5900  and Tg (ry-caax)  permits osterix/sp7 promoter as Tg (sp7:EGFP)b1212 [medaka osx-mCherry [Ola. Sp7:NLS-GFP)zf132 [Reporter lines using FP)b1212 , medaka -mCherry , and Tg FP)zf132  are usefFP)zf132 .CTSK-DsRed [Ctsk YFP [Tg (ctsk:mEGFP) transgenic line has been used in a multitransgenic approach together with heat-shock-induced receptor activator of nuclear factor kappa-B ligand (RankL) expression. The RankL-mediated osteoclast differentiation causes an osteoporotic phenotype in medaka embryo [Reporters using cathepsin K promoter as SK-DsRed  or Ctsk Ctsk YFP  have beea embryo .Other transgenic lines have also been applied for joint studies. For example, trps1j1271aGt expresses GFP in joint regions of wild-type fish and it has been used to elucidate the regulatory pathways of differentiation and organization of joint cells in physiological and pathological conditions .In fish, some characteristics such as bone turnover, repair, and remodeling of the adult bone tissue cannot be found in embryonic or juvenile stages. In addition, adult fins and scales represent unique anatomical features with undoubted advantages like transparency and the presence of mineralized tissue similar to human lamellar bone. The same dyes used for live embryo bone tissue staining can be used in adult fish, on both live fish and fixed sample to highlight the scale mineral matrix  or caudaThe identification of zebrafish mutants that recapitulate human mineralized craniofacial, dental, and skeletal system disorders can be used at adult stage as models to study the progression and the pathological effects (primary or secondary).Chihuahua was isolated in a forward-genetics screen of adult fish searching for skeletal abnormality using X-ray [Chihuahua can be considered as a model of human osteogenesis imperfecta useful to elaborate new therapeutic strategies [Years ago, zebrafish mutant ng X-ray . Heterozng X-ray . The samrategies .Few years ago, a large-scale forward genetic chemical mutagenesis screening led to the identification of 7 adult homozygous recessive mutants with skeletal disorders including craniofacial defects, suture fusion, morphological or numerical alteration of skeletal elements, and scoliosis .The regulatory mechanisms of postembryonic development are still poorly understood. Recently, a screening for phenotypes affecting the adult zebrafish has been performed with the identification of 72 adult viable mutants showing defects in skeleton and pigmentation .These mutant models can be used in the adult stage to study long-term complications of bone diseases as well as the pathogenesis of defects in postembryonic development.Fibrodysplasia ossificans progressiva (FOP) is a rare human skeletal disease caused by constitutively activating mutations in the gene ACVR1. Heterotopic ossification (HO) throughout skeletal muscle, tendons, and ligaments has been reported in human patients with generation of bone malformations, vertebral fusions, and osteochondromas .Since the embryonic overexpression of constitutively active Acvr1 in zebrafish results in embryonic lethality, heat-shock inducible expression constructs for acvr1Q204D have been used to create a conditional mutant model of FOP in adult zebrafish .Progressive bone loss is a serious side effect of the long-term permanence in the absence of gravity. Clinical studies on astronauts revealed that an average of 1 to 2 percent of bone mass can be lost each month . SeveralIt is known that physical exercise modulates bone mass in all vertebrates; nevertheless, the mechanisms are still largely unknown. We can suggest that the mechanical stress generates a musculoskeletal adaptation stimulating sensor systems localized on bone cells , 85.Adult zebrafish represents an innovative model to study the effect of the mechanical loading on bone mass and metabolism, in absence of gravity charge.Recently, an increased physical exercise has been applied to adult zebrafish for four weeks using a specific swim tunnel. The results demonstrated that the exercise stimulated increases in bone-forming osteoblasts, bone volume, and mineralization .About cartilage tissue, it has been demonstrated that chondrocytes possess a high-rate turnover in zebrafish adult spine and that age but not short-term intensive exercise can modulate spinal BMD . The zebThe knowledge of the molecular mechanisms of mechanical adaptation in adult bone can improve the development of new strategies of prevention and treatment in human diseases like osteoporosis.Zebrafish is able to fully regenerate fins via dedifferentiation, proliferation, and redifferentiation of bone-forming cells. The growth of new skeletal structures is coordinated with other tissues  in a complex regulatory mechanism which is still to be understood . These sAdult fin regeneration can be analyzed also in pathological models like type 1 diabetes as bone complication of metabolic disease. An impairment of caudal fin regeneration has been observed in hyperglycemic zebrafish established by streptozotocin injection .The skull of adult zebrafish can be also used as a model for regeneration studies through the trepanation of calvarial bones. The hole in the bone tissue is repaired by a metabolic reactivation of surrounding osteoblasts . These dIt is known that several zebrafish cranial bones are formed by endochondral ossification. To elucidate the mechanisms of repair in cartilage-derived bones as well as their origins in the periosteum, a large-scale regeneration model has been established in adult jawbone. After resection of zebrafish jaw, a mixed cartilage/bone cell type emerges from bone-lining cells and starts to produce cartilage matrix early and mineralized matrix later .in vivo the osteochondral regulation during cell specification and function.Chondroid bone repair processes can also coexist with intramembranous ones during bone healing. This model is elective to study in vivo the direct differentiation processes from adult stem cell-like precursors to bone-forming cells. The presence of osteoclasts in the scale matrix and the transparency of the anatomical structure encourage the use of this model to investigate the role of catabolic phenomena in bone tissue regeneration [The adult zebrafish scales are also able to regenerate rapidly after loss. Recent data indicated that osteoblast-precursor cells differentiate and proliferate establishing a primordium of the new scale. In posterior scale regions, mineralized grooves (radii) are radially formed during the deposition of new rings . This moneration , 95.Since zebrafish caudal fin possesses unique characteristics of accessibility and transparency, it has been introduced to investigate the reparative capacity of adult bone tissue.csf1ra mutant, which has reduced osteoclast numbers, due to a reduced remodeling function [Staphylococcus aureus has been investigated showing that when fractures are infected, neutrophils are retained and delayed repair due to a prolonged inflammatory state [A caudal fin ray crush injury has been used to develop a model of vertebrate long-bone fracture, which easily analyzes mineralized matrix deposition and time-regulated gene expression can be easily analyzed during the repair process . The bonfunction . In addiry state .The regeneration program, typical of the extensive fin injury, should not be activated for a single ray fracture but rather a tissue repair process, much more similar to a wound healing. The identification of the key processes that regulate the tissue response after bone fracture may contribute to the improvement of bone repair in humans.Osteoporosis is a bone disease in which mineralized tissue becomes weak and the risk of fracture increases significantly, especially in the spine. Zebrafish spine, in addition to being anatomically and histologically similar, is also axially loaded like humans and shows similar pathologies to humans during ageing .An osteoporotic phenotype is induced in the spine by overexpression of RankL and GFP in transgenic medaka lines with heat-shock-controlled osteoclastic promoter. When RankL is induced in adult stage, osteoclasts migrate from the intervertebral regions to the centra of the vertebral bodies causing severe degradation of the mineralized matrix .It is known that an accumulation of elevated iron in the body is an independent risk factor for osteoporosis. Adult zebrafish has been used to model an osteoporosis phenotype using high iron stress . Iron overload decreases bone mineralization in axial skeleton of adult zebrafish. In addition, osteoblast-specific gene expressions were found significantly modulated after iron exposure .Adult zebrafish scale has been recently introduced as read-out system for bone metabolism studies , 101. ThRecently, secondary osteoporosis has been reproduced in adult zebrafish after treatment with prednisolone , a glucoZebrafish has been recently introduced to model chronic diseases of metabolism such as obesity and type 2 diabetes and, in particular, to identify genetic variants associated with these conditions in humans .In fact, zebrafish represents a powerful animal model to study the metabolic diseases and their complications ; neverthIt is known that the skeletal metabolism is affected in diabetes patients  but the in vivo the molecular mechanisms of bone complications as demonstrated by the analysis of advanced glycation end-products (AGEs) and PTH levels in the fish blood [To clarify the correlation between blood glucose level and bone metabolism, a chronic hyperglycemia was established in a new zebrafish model of type 2 diabetes by glucose administration in the water . The incsh blood . A hyperGlycyrrhiza glabra roots, significantly prevents the onset of the hyperglycemia in adult zebrafish and systemic alterations such as increase of AGEs and PTH levels in the blood [Recently, zebrafish models of diabetes have been used to test glucose lowering natural compounds . One of he blood . Intereshe blood .This study confirmed that hyperglycemic zebrafish is a powerful tool to screen new compounds active on blood glucose level and bone complications.in vivo are linked to metabolic impairment such as adipokines (leptin) overproduction and higher aromatase activity [It is known that the risk and the number of some fractures  are higher in obese people. Bone mineral index (BMI) and bone mineral density (BMD) are correlated and the mechanisms of this association activity .Since lipid metabolism and the adipogenic mechanisms are conserved between fish and mammals, zebrafish has been developed as an important model system to study fatty acid metabolic syndrome  and obesRecently, an obese adult zebrafish has been created by high-fat diet administration to study the metabolic relationship between fat and bone . VisceraIn fact, the decrease in adiponectin and increase in leptin, which are common features in human and other obesity animal models, are associated with bone catabolic processes , 117.In obese fish, osteoporosis has been found in scales as large bone resorption lacunae associated with an intense TRAP activity, whereas ALP was found decreased. The gene expression analysis supports the hypothesis that the unbalance of the RANL/RANK/OPG pathway in obese fish alters bone metabolism in favor of osteoclastic activation .in vivo the molecular mechanisms of metabolic alterations and bone complications in human obese patients.The study of adult obese zebrafish suggests that fat accumulation leads to an alteration of glucose metabolism (insulin-resistance) with generation of AGEs and unbalanced production of important adipokines such as adiponectin and leptin. These metabolic changes synergize to alter bone metabolism in zebrafish scales inducing an osteoporotic-like phenotype. The zebrafish obesity model can be used to elucidate Several imaging resources may be used to facilitate the investigations on the adult zebrafish models of bone disease contributing to the knowledge of the pathogenic mechanisms of human counterpart. A lot of imaging resources can be adapted for small animal models like rodents or fish.Recently, Time-Gated Optical Projection Tomography (TGOPT) has been used in adult zebrafish to visualize in 3D the anatomical body structure without chemical contrast .μCT), permitting the analysis of the skeleton and the determination of BMI for each bone scan section. Total-body μCT scans can be applied in pharmacological studies where the 3D reconstruction of the zebrafish bone system is used to detect alterations in bone structures after particular treatments like dietary supplementation [In addition, whole adult zebrafish can be scanned by microcomputed tomography . Recently, bone defects due to a prednisolone treatment have been quantitatively evaluated using the SD-OCT images at different time points during a period of 21 days [ 21 days .X-ray radiography has been already introduced in adult zebrafish mutant screening to detect abnormalities in skeletal morphology .Danio rerio (zebrafish) is an elective model organism for the study of vertebrate skeletal biology because of its high degree of homology between human and zebrafish in terms of structure, function, and regulation mechanisms. Zebrafish embryos, because of the optical clarity, small size, and fast development, can be easily used to (1) study osteogenesis evaluating differentiation, matrix deposition activity, and cross-talk of skeletal cells, (2) create and isolate mutants modeling human bone diseases, and (3) test in high-throughput screenings new chemical compounds for the ability to revert bone defects. On the other hand, the adult zebrafish represents a different and powerful resource useful for pathogenic and therapeutic studies about adult human bone diseases because some functions like bone turnover, repair, degeneration, and metabolic responses are not mature in embryos. For these reasons, the adult zebrafish represents an innovative and readily available resource for studying (1) the regulatory mechanisms of adult bone metabolism at cellular and molecular levels, (2) the pathogenesis of bone diseases, and (3) bone complications of different human diseases. Several examples of bone disease models in adult zebrafish have been generated in the last years.Many disease models with bone alterations have been established in adult zebrafish such as long-bone fractures, osteoporosis, genetic disease as osteogenesis imperfecta, diabetes, and obesity.In conclusion, zebrafish embryos and adults should swim together to allow us to understand bone physiology and pathology from all points of view.


The haploid female gametophyte (embryo sac) is an essential reproductive unit of flowering plants, usually comprising four specialized cell types, including the female gametes . The differentiation of these cells relies on spatial signals which pattern the gametophyte along a proximal-distal axis, but the molecular and genetic mechanisms by which cell identities are determined in the embryo sac have long been a mystery. Recent identification of key genes for cell fate specification and their relationship to hormonal signaling pathways that act on positional cues has provided new insights into these processes. A model for differentiation can be devised with egg cell fate as a default state of the female gametophyte and with other cell types specified by the action of spatially regulated factors. Cell-to-cell communication within the gametophyte is also important for maintaining cell identity as well as facilitating fertilization of the female gametes by the male gametes (sperm cells). These four cell types are specified from the eight haploid nuclei that have descended from the FM. After the first mitotic division of the FM . The female gametophyte (FG), called the embryo sac, produces the female gametes and usually is obscured within the maternal, sporophytic ovule . Fusion 6. How and when do the nuclei and the resulting cells of the gametophyte acquire fate information? What external signals are required, and how do cells communicate with each other to define or confirm these fates? These questions have been tackled by assessing mutants or ectopic expression lines which alter cell identities, observed by morphological changes, and monitored with the use of fluorescent or colorimetric reporter genes expressed in specific cell types  and vacuole position. Their molecular differences have been analyzed in RNA profiling experiments and these differences reflect their different roles in the FGTorenia fournieri gametophytes shows that at late FG4 (four-nucleate stage), when there are two nuclei at the micropylar end, these nuclei have a polar arrangement along the micropylar-chalazal axis11. The nucleus closest to the micropyle was observed to give rise to the synergids, while the nucleus closest to the central vacuole gave rise to egg and polar nucleus. This arrangement of FG4 nuclei has also been observed in fixed Arabidopsis ovules12. Differing cell fates of sister nuclei may result from asymmetric distribution of a molecular signal within the embryo sac or from an asymmetric external sporophytic signal. There are multiple lines of evidence for the importance of mobile signals in FG patterning at the micropylar pole where the egg cells and synergid cells are located (TRANSPORT INHIBITOR RESPONSE (TIR) family andAUXIN RESPONSE FACTOR (ARF) family—were downregulated or inactivated in the early developing embryo sac15. Conversely, ectopic expression of the auxin biosynthesisYUCCA genes appears to shift micropylar cell fates toward the chalazal end of the gametophyte, conferring synergid and egg cell marker expression onto the central cell and antipodal cells14. Despite differing conclusions about the presence of auxin inside the embryo sac, studies are in agreement that auxin accumulation occurs in the adjacent sporophytic cells of the nucellus at the micropylar end during gametogenesis, consistent with localization of PIN and AUX1 auxin transporters in the sporophyte and gametophyte, respectively17. That auxin either directly or indirectly acts as a signaling molecule for micropylar specification, in particular for synergid cell fate, is also supported by the phenotypes ofyucca mutants, in which synergids exhibit egg cell attributes14.Live imaging of developinglocated . The plaaltered meristem program 1 (amp1) mutant, synergid cells are converted to functional egg cells at high frequency18, among other pleiotropic effects. Interestingly, sporophytic expression ofAMP1 is sufficient to rescue this phenotype.AMP1 is detected only in the integuments early in gametophyte development and in synergids after cellularization. Therefore, AMP1 appears to mediate a mobile signal that promotes synergid identity, and in the absence of that early signal, egg cell fate is adopted. AMP1 protein is a membrane-anchored carboxypeptidase protein localized to the rough endoplasmic reticulum (ER)19. The protein has been associated with translation repression by microRNAs (miRNAs)21 and is also important to repress biosynthesis of cytokinins22. Crosstalk between cytokinin and auxin affects developmental modules in many parts of the plant; in many cases, the balance between these hormones is essential for correct patterning of cell types , an ER-localized histidine kinase that can activate cytokinin responses constitutively29.cki1 mutants show loss of central cell and antipodal identities and expansion of egg cell and, in some cases, synergid attributes, suggesting that CKI1 suppresses micropylar cell fates31.CKI1 expression, initially present at both poles through FG3, is quickly restricted to the two nuclei of the chalazal end at FG4. This polarity of expression is maintained through the next nuclear division (FG5 stage). After the chalazal polar nucleus and its associated ER migrate toward the micropylar polar nucleus at stage FG5,CKI1 expression continues in the resulting diploid cell as well as in the antipodal cells at the chalazal end. Ectopic expression ofCKI1 is sufficient to induce central cell fate in the egg cell and synergids and produce seeds with multiple ectopic endosperms but lacking embryos. Therefore,CKI1 appears to specify central cell identity while restricting micropylar cell fates , which then activate downstream transcription factors. Specifically, in the FG, AHP2, 3, and 5 are required for CKI1 function32. Transcription factors that are potential targets of this pathway include the MADS box–containing genesAGL80 andDIANA/AGL61, which are known regulators of central cell–specific pathways35. Transcription factorMYB119 is also a likely target of CKI1 regulation and acts redundantly withMYB64 to promote cellularization36.myb64 myb119 mutants fail to cellularize and they show continued nuclear divisions and an expansion of central and antipodal cell fates. It is likely that the absence of cell membranes allows expansion of central cell and antipodal cell identity factors and suggests thatCKI1 not only promotes chalazal identity but also a mechanism to limit that identity to the appropriate space.A key differentiation factor for the nuclei at the chalazal end of the FG isl fates . SimilarCKI1 is expressed in antipodal cells and is required for antipodal cell specification, as antipodal cells acquire egg cell attributes incki1 mutants. At the same time,CKI1 does not alter antipodal cell fate when overexpressed; that is, antipodal cells are not re-specified as central cells29. This suggests thatCKI1 action must be redirected in these cells by an additional antipodal specification factor acting at the chalazal end  gene family have been suggested as egg cell determinants because of their high expression in egg cells and ability to activate egg-like transcription profiles when ectopically expressed41. In addition, loss of the putatively orthologous single-copy gene inMarchantia polymorpha,MpRKD, leads to failure to develop mature egg cells43. Thus,RKD genes seem to have a conserved role in egg cell differentiation. However, recent examination of theRKD gene family has suggested a complex role in Arabidopsis. Thus far, onlyRKD2 was shown to be specific to mature egg cells, but other family members are expressed in egg and other cells of the gametophyte44.RKD1 and2 are capable of activating aspects of the egg cell transcriptome ectopically in protoplasts, callus, and sporophytic cells of the ovule40. These overexpression phenotypes suggested thatRKD1 andRKD2 are activators of egg cell identity, but neither the single mutants nor a double mutant led to obvious changes in cell type in the gametophyte44. Investigating redundancy with other gene family members showed thatRKD2 acts from the earliest stages of FG development, as double mutants withRKD4 andRKD5 cause significant FM arrest as well as loss of egg cell identity markers44. Taken together,RKD genes of Arabidopsis seem to act redundantly at multiple stages of reproductive development, including proper progression from FM to FG, and in activation of egg cell differentiation. Considering their early action in the FG and ectopic expression results, we suggest thatRKD genes may help to create a default egg cell–like state in the developing FG and may continue to be important for egg cell differentiation later. In this scheme, differentiation into cell types other than the egg cell would then require additional cell factors  whose actions are governed by nuclear positions at cellularization.Egg cell fate predominates in the absence of46, so we present only a brief outline here. A complex set of pollen attractants, and structural changes to cell membranes are produced by synergid cells, regulated in part by specific expression ofMYB98 in mature synergids49. Recently, central cell transcription factorsCENTRAL CELL GUIDANCE (CCG) andCCG BINDING PROTEIN 1 were shown to interact with each other and other binding partners to influence expression ofMYB98 as well as expression of small mobile peptides that themselves may be pollen tube attractants51. After entry of the pollen tube, fusion of sperm with egg and central cell requires egg cell–specific secreted peptides of theEGG CELL 1 (EC1) family53. Recent evidence involves chromatin remodeling factors and the transcription factorSUPPRESSOR OF FRIGIDA 4 in regulation ofEC1 genes54. Pollen tube reception destroys one synergid, leaving the other intact and capable of attracting another pollen tube, but only if the gamete fusions from the initial pollen tube fail57. Sperm cell and egg cell fusion signals successful fertilization via ethylene signaling58, and the newly fertilized central cell (now endosperm) fuses with the remaining synergid, thereby diluting its ability to attract pollen tubes59. Central cell–specific Polycomb repressive complex genes are required for this fusion, indicating that proper specification of the central cell is one essential aspect of this process. In summary, successful double fertilization requires multiple processes and relies on specific gametophytic cell types. Pollen tube guidance is provided primarily by the synergids but also the central cell while pollen tube entry occurs through the synergid cells. Sperm cell fusion with the two female gametes requires factors provided by the egg cell; finally, suppression of the pollen tube attraction signal occurs by fusion of the central cell with the persistent synergid cell. Thus, successful double fertilization to produce a seed is an orchestrated process involving multiple interactions of the synergid cells, the egg cell, and the central cell. As discussed in this review, the overall themes of how these different cell types are specified are emerging gradually from the multiple approaches employed by several different laboratories. However, the molecular details are still rudimentary as compared with those of other developmental processes such as floral or meristem development, and there is a vital need for further elucidation of the relevant developmental pathways in the FG, given its critical importance to flowering plant reproduction.The correct specification of cell fates is important not only for formation of the female gametes but also for double fertilization, a process that requires the participation of three of the four cell types in the FG. This process has been reviewed extensively in recent articlesaltered meristem program 1; CCG,CENTRAL CELL GUIDANCE; CKI1,CYTOKININ INSENSITIVE 1; EC1,EGG CELL 1; ER, endoplasmic reticulum; FG, female gametophyte; FM, functional megaspore; RKD,RWP-RK DOMAIN CONTAINING.AHP, Arabidopsis phosphotransfer protein; amp1,


The demographic history of anatomically modern humans (AMH) involves multiple migration events, population extinctions and genetic adaptations. As genome-wide data from complete genome sequencing becomes increasingly abundant and available even from extinct hominins, new insights of the evolutionary history of our species are discovered. It is currently known that AMH interbred with archaic hominins once they left the African continent. Modern non-African human genomes carry fragments of archaic origin. This review focuses on the fitness consequences of archaic interbreeding in current human populations. We discuss new insights and challenges that researchers face when interpreting the potential impact of introgression on fitness and testing hypotheses about the role of selection within the context of health and disease. Homo sapiens emergence was recently challenged by Hublin et al. [H. sapiens maxilla of 177 to 194 kya in Misliya Cave, Israel. All these studies suggest that the members of the H. sapiens clade left Africa earlier than previously thought, probably in several waves of OOA migration at different stages of evolution. Classical “pure” OOA assumes that admixture with other archaic populations such as Neanderthals or Denisovans, present at the time of the rise of AMH, either did not occur or was negligible [The demographic history of anatomically modern humans (AMH) is complex, and involves a large number of migrations, genetic admixtures and introgressions, population extinctions and genetic adaptations, which overlap both in time and in space see . Due to n et al. , who foun et al. . Similarn et al.  describegligible .However, genomic studies of ancient DNA have revealed that AMH interbred with other hominid lineages, such as Neanderthals and Denisovans, present in Eurasia since 300 kya up to 30–50 kya. The admixture with Neanderthals occurred around 37–86 kya, and most likely between 47 and 65 kya ,18,19,20New studies based on current genetic diversity are suggesting that the events of archaic introgression in AMH did occur after out of Africa migration with other hidden ”ghost” archaic populations . The maiIntrogressed alleles in a foreign genetic background frequently have negative fitness effects regardless of the amount of adaptive introgression. Martin and Jiggins  made twoDisproportionate roles for sex chromosomes in species differences and hybrid incompatibility constitutes a consistent pattern in speciation ,35. The FOXP2) gene [AMY1 gene, encoding an amylase enzyme responsible for starch digestion [Evidence for the role of purifying selection in shaping the introgression landscape comes from particular categories of genes experiencing different amounts of introgression as previously demonstrated for non-human species ,41,42,43P2) gene , mutatioP2) gene . Similarigestion . In contigestion ,51 and tigestion . This haigestion . Moreoveigestion ). Anotheigestion  on smalligestion   also show the signature of positive selection as the result of adaptation to diverse habitats with different degree of insolation  [ERAP2, involved in susceptibility to Crohn’s disease; CCR1, limiting leukocyte recruitment and preventing inflammatory responses; HLA-DQA1, associated with susceptibility to celiac disease; and TLR1, associated with markedly lower levels of inflammatory response gene expression [TLR7/8 stimulation and influenza virus [DARS associated with neuroinflammatory and white matter disorders [OAS locus apparently associated with diverse flavivirus resistance phenotypes [PNMA1 harboring a response eQTL for influenza virus and stimulating interferon production [TNPO3 in the brain is associated with multiple autoimmune phenotypes [Increasing evidence suggests that regulatory variants play a central role in adaptive processes ,87,88. A tissues . There a tissues ,72,89. Drelevant ,89. Archnucleus) . Other epression ,72. Appaza virus . Furtherisorders ; the arcenotypes ; and PNMenotypes . All theenotypes . FurtherCCR) gene family constituting the risk alleles for celiac disease, which was possibly maintained by selective forces in early European population. Furthermore, population genetic analyses have shown that the high frequency of several risk alleles of genes associated with celiac disease such as IL12A, IL18RAP and SH2B3 [ZNF365D gene present in ~32% of Europeans and absent from Africans, which was inherited from Neanderthals and is associated with a higher risk of Crohn’s disease [TLR6-1-10 inherited from Neanderthals and Denisovans and present in Europeans and Asians has been associated with greater susceptibility to allergies [However, whatever the potential benefits of archaic introgression in the past, alleles of Neanderthal origin have been also associated with several neurological, dermatological, and immunological phenotypes, indicating an influence of ancient admixture on current disease risk in humans ,92,93. Fnd SH2B3  in Europnd SH2B3 ,100. Anollergies .Further investigations are required, but the studies published to date have provided invaluable resources and increased our understanding of the molecular and cellular processes underlined by introgressed genetic variants and different selective regimes acting on them.The ongoing deluge of sequencing data from thousands of individuals and different populations worldwide, including some archaic hominins and ancient AMH genomes, has provided new insights into the evolutionary history of our species. Genomic studies of introgression between early Eurasians and archaic human species, such as Neanderthals and Denisovans, are beginning to offer novel insights into the evolutionary and phenotypical consequences of hybridization. There is quite common evidence for widespread selection against introgression across the genome, but adaptive introgression may also be considered an important force driving adaptation of modern humans to new environments. However, additional human dataset advances, integration of different sources of information and development of new statistical and analytical methods are critical for understanding the biological and medical implications of such signals of selection.In the case of integrating different sources of information, studies of genetic variants with regulatory effects on gene expression (eQTL) have already provided insight into the genetic and evolutionary determinants of population phenotypic diversity . One of In the case of new methods, the challenge for the future will be to develop robust statistical models and computational methods for detecting selection, quantifying the frequency of adaptive introgression more widely and understanding the circumstances where it is likely to play a predominant role in adaptation. An exciting future prospect is that our interpretations of observations in nature will be aided by simulation studies  and empiHomo, and the ways our genetic and non-genetic makeup, together with changes in our environment and cultural behaviors, influence phenotypic variation in both health and disease.In conclusion, the integration of all of these datasets into a clinical, epidemiological, and population genetics framework will provide new insights on the history of adaptations in the genus


Arabidopsis thaliana and in other species such as rice or maize. Chromosome mutants produced in wheat provided also valuable information. Nowadays, many research groups are using translational biology approaches to improve the sustainability of food production in crops based on the manipulation of meiotic recombination. Because many crops are polyploids, complications of the meiotic behavior derived from the polyploid condition are also in the focus of a number of research projects. The purpose of this Research Topic was to provide a platform for the publication of updated information and high-quality research papers, in both model species and crops, which will represent a guide addressing our fundamental knowledge of meiosis as well as its implications for plant breeding. After a large response, which reflects active research being undertaken, we published a total of 21 papers, including 1 Mini-Review, 3 Reviews, 1 Methods, and 16 Original Research. These papers are grouped in the following items: i) new approaches and methods in the study of meiosis; ii) meiotic recombination; iii) meiosis in polyploids; iv) chromosome segregation; and v) other aspects of meiosis.Advances in the study of plant meiosis produced in the last three decades were based mainly in the isolation of meiotic mutants and genes in the model species Lambing and Heckmann, which include super-resolution microscopy and live cell imaging that are extensively used in understanding chromosome dynamics and plant meiosis progression, application of sequencing-based techniques to map crossovers (COs) and their correlation to gene expression landscapes, as well as the proteomic analysis to profile proteins involved in meiosis. Capilla-Perez et al. report a recent development of genetic resources by creating a new homozygous mutant library for researchers to perform functional analysis of meiotic genes. Eight hundred ninety-seven homozygous Arabidopsis mutant lines are among this collection, including those targeted 26 previously reported meiotic genes. Dreissig et al. use single pollen nucleus sequencing to study meiotic recombination events and segregation distortion caused by postmeiotic processes. Genome wide distribution of recombination uncovered similarity of recombination landscapes between barley pollen and double haploid plants; but the segregation distortion is high in double haploid population comparing to almost absent in pollen. Sepsi et al. combine immunolabeling, fluorescence in situ hybridization, and confocal microscopy to simultaneously detect the nuclear localization of proteins and specific DNA sequences within chromosomes. Construction of 3D images has shown detailed chromosome structures and critical proteins associated with meiosis in rye. Also using rye system, Hesse et al. report a technique combining scanning electronic microscopy and fluorescence microscopy to examine ultrastructure and dynamics of synaptonemal complex (SC) components during meiotic pairing and synapsis. The super high-resolution technique advances the ability of researchers to study chromosome dynamics and configuration during meiosis with great details at the molecular and subcellular levels.i) New approaches and methods in the study of meiosis presents one review paper and four technological articles outlining recent advancement of technologies for plant meiosis studies ranging from genomic analysis, single cell sequencing to super-resolution and 3D imaging investigation of chromatin dynamics. All tools available for studying meiosis have been reviewed comprehensively by Okagaki et al. compile historically accumulated evidence to explain that in maize, unlike the situation in other model systems, many recombination hotspots are located within genes. In some of these genes there is a gradient of recombination (polarity) with higher CO rates at the ends (5′ or 3′). As well as in Arabidopsis, in maize, the fraction of DSB hotspots resolving as COs is small (less than 4%). The message from this detailed review is that the recombination process of a species does not necessarily fit to those of the model species described. In addition, it is necessary to compile data derived from different methodological approaches in order to have a global view of how the meiotic recombination process takes place. Meiotic recombination is a process highly regulated by specific genes. Among these genes are those involved in processing DSBs. The work by Wang et al. describes the consequences arising from the absence of ZmCOM1 during maize meiosis. They demonstrate that this protein is indispensable to ensure the bouquet formation and the assembly of the SC. In addition, maize plants deficient for this protein display problems during mitosis. According to their observations, the function of COM1 is conserved in plant meiosis. However, during the cell cycle, its function seems to be more important in maize than in plants with smaller genomes. Hu et al. analyze the role of the replication factor C–like protein OsRAD17. This protein, together with the 9-1-1 complex, is essential for DSB repair during rice meiosis, and collaborates with the meiosis-specific ZMM proteins to ensure correct homologous pairing and synapsis. In plant crops, many genes that contribute to agronomically important traits are located within CO suppressed regions. One of the factors that regulate CO frequency is the anti-CO protein Fanconi Anemia Complementation Group M (FANCM). The absence of this protein produces a 3-fold increase in CO formation in Arabidopsis, although this increase is not uniform along chromosomes. Blary et al. demonstrate that the anti-CO function of FANCM is also conserved in the crop species Brassica rapa and B. napus, highlighting the potential application of this gene in plant breeding programs. Zelkowski et al. prove that the meiotic function of the SMC5/6 complex that has been demonstrated in yeasts, worms, and mammals is conserved in plants. Specifically, one δ-kleisin subunit of this complex, AtNSE4A, is essential for the resolution of meiotic recombination intermediates during the first meiotic division in Arabidopsis. Furthermore, during prophase I, the NSE4A protein colocalizes with the central element of the SC (ZYP1) in Arabidopsis, B. rapa, and rye, revealing also a possible role in synapsis.ii) Meiotic recombination is initiated by the formation of DNA double-strand breaks (DSBs). A subset of these DSBs are repaired as COs, reciprocal exchanges of genetic information between homologous chromosomes, allowing the formation of genetically unique gametes. COs are non-randomly distributed along chromosomes, there are regions that recombine more than average (hotspots), while other regions are completely devoid of COs. Ph1 gene, the study of the meiotic behavior of alien chromosomes added to wheat, and the identification of homoeologous pairing between wheat and Elytrigia elonagata chromosomes. Parra-Núñez et al. report the formation of more multivalents than expected under the assumption of simple random-end pairing in autotetraploids of two accessions of Arabidopsis. This suggests more than two autonomous synapsis initiation sites per chromosome and more than one partner switches per tetrasome. The multivalent frequency decreases in the tetraploid obtained after duplication of the hybrid between the two ecotypes, probably because of heterozygosity. Preferences for chiasma formation between homologous versus identical chromosomes in tetrasome 3 but not in tetrasome 2 of the duplicated intraspecific hybrid, reveal the existence of chromosome-specific mechanisms affecting the partner selection. Rey et al. use two TILLING mutants and one CRISPR mutant of the TaZIP4-B2 gene on chromosome 5B to produce interspecific wheat × Aegilops variabilis hybrids whose meiotic phenotype identifies ZIP4 as the Ph1 gene. The frequency of interspecific homoeologous recombination induced by the ZIP4 mutations increases after irrigation of the plants with magnesium of a nutrient solution. Naranjo argues that the meiotic behavior of individual rye chromosomes changes when they are introgressed into a wheat background. The pattern of chromatin organization at early prophase I is affected, especially for chromosome 4R, which increases its length much more than any other rye chromosome at leptotene-zygotene. Telomeres clustering, but not their dispersion, is depending of the chromosome conformation, which has implications on synapsis and recombination. Chiasma formation is affected in some chromosome arms that show complete synapsis. Calderón et al. use addition lines of barley and Hordeum chilense chromosomes into wheat to produce double monosomic additions carrying pairs of homoeologous or non-homoeologous Hordeum chromosomes. In the presence of Ph1, only the Hordeum homoeologous pairs recognize each other in subtelomeric regions and complete synapsis. However, they do not form chiasmata suggesting that Ph1 suppresses homoeologous CO formation. He et al. use genomic in situ hybridization to identify the chromosomes of hexaploid wheat and decaploid E. elongata in interspecific hybrids and backcrosses of the hybrids with wheat. Some associations at metaphase I between chromosomes of both species are produced supporting the occurrence of interspecific homoeologous recombination. This agrees the hypothesis that Ph-suppressor genes, which promote homoeologous recombination, are present in E. elongata.iii) Meiosis in polyploids includes papers concerning the analysis of preferences on interactions between homologous and identical chromosomes in autotreploids, the identification and mode of action of the wheat Easterling et al. use 3D cytogenetic analysis of meiotic chromosome dynamics in hop (Humulus lupulus) pollen mother cells. The configuration of chromosomes in hop male meiosis include multiple, atypical, non-disomic chromosome complexes detected as aneuploidy, segmental aneuploidy, or chromosome rearrangements, which implicate multiple contributing factors to segregation distortion in hop. Through analysis of multiple centromere misdivision derivatives of a translocation between the supernumerary B chromosome and the short arm of chromosome 9 in maize, Han et al. report that the property size of a centromere does not dramatically affect its segregation or its ability to progress to the poles at the end of cell division. The biochemical features of centromeres are likely the factors for the adjustment in response to the cellular conditions. Sudden temperature changes often lead to abnormal chromosome segregation. Liu et al. use the model system A. thaliana to explore the mechanisms behind the cold-induced male meiotic restitution. Findings from this research implicate that GA-DELLA signaling is not the critical factor responsible for the cold-induced abnormal chromosome segregation.iv) Chromosome segregation includes three papers focusing on both chromosomal properties and environmental factors that impact on chromosome segregation. Fuchs et al. discuss major anthropogenic factors affecting meiosis in plants, including environmental stresses, agricultural inputs, heavy metals, pharmaceuticals and pathogens. In most cases, the anthropogenic impacts on meiosis are altered recombination frequency and distribution, severe chromosomal fragments caused by stickiness and bridges, precocious movements, and unequal separations resulting in micronuclei and aneuploidy, as well as spindle aberrations. Polyploid speciation is closely related to the regulation of meiotic recombination, which is reviewed by Pelé et al. To achieve speciation success of a polyploidy species, three aspects of meiotic recombination should be guaranteed: the regulation of the genetic variability of newly formed polyploids, the maintenance of the allelic combinatorial possibilities in the following generations, and the faithful segregation of multiple homologs or homoeologs in auto- or allopolyploids. During speciation, different patterns of recombination, coupled with different polyploid formation pathways, cause varied level of heterozygosity. The formation of a polyploidy species with high level of heterozygosity will produce more genetically diverse progenies, therefore improving its environmental adaptability through different natural selections. In the third review, Bolaños-Villegas and Argüello-Miranda mainly summarized the possible technical approaches to manipulate meiosis in orphan crop breeding. They proposed that genome haploidization through modified CENH3 or the apomixes-inducing genes could be a rapid option to create new crosses in tropical crops. Moreover, gene editing of some key meiotic genes, such as ASY1, FANCM, RECQ4, and PH1, might facilitate produce new varieties that are enriched in desirable wild traits.v) Other aspects of meiosis include three reviews that individually focus on the influences of exogenous anthropogenic factors in plant meiosis, the effects of recombination regulation on speciation success of polyploidy species, and the technical approaches to engineer key meiotic genes in tropical crops. Plants now grow on environments that are frequently exposed to anthropogenic factors capable of modulating their meiotic processes. In the first review, TN, CC, ZC, and MP wrote the paper.Work in the laboratory of TN and MP was supported by grant AGL2015-67349-P from Dirección General de Investigación Científica y Técnica, Ministerio de Economía y Competitividad of Spain. Research in the laboratory of CC is sponsored by the National Science Foundation (NSF-IOS-1546792).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Structural variants (SV) are changes in the genomic landscape that can alter gene expression levels and thus lead to disease development. The most common and best studied SVs in hematological malignancies are chromosomal translocations. Here, parts of two genes that are normally on different chromosomes come into close proximity due to a failure in DNA repair. As a consequence, fusion proteins which show a different function and/or cellular localization compared to the two original proteins are expressed, sometimes even at different levels. The identification of chromosomal translocations is often used to identify the specific disease a patient is suffering from. In addition, SVs such as deletions, duplications, inversions and single nucleotide polymorphisms (SNPs) can occur in hematopoietic cells and lead to their malignant transformations. Changes in the 3D genome structure have also recently been shown to impact disease development. In this review, we describe a variety of SVs occurring in different subtypes of hematological malignancies. Currently, most therapeutic approaches target fusion proteins which are the cellular product of chromosomal translocations. However, amplifications and SNPs also play a role in disease progression and can be targeted. We present some examples for different types of structural variants and how they are currently treated. Hematological malignancies are a group of diseases affecting the blood or immune system that are derived from either the myeloid or the lymphoid lineage, respectively. The most common myeloid malignancies are acute or chronic myeloid leukemia (AML or CML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN), while the most common lymphoid-derived diseases are acute or chronic lymphoid leukemia (ALL and CLL), lymphomas and multiple myelomas .A major cause that is common to hematological malignancies is the presence of chromosomal rearrangements. The detection of copy number variations and other quantitative aberrations yielded insights into tumor pathogenesis in leukemias and lymphomas, and the recent development of high-throughput DNA sequencing allows the precise detection of chromosomal “breakpoints” –6. ChromChromosomal translocations often oppose one gene to the regulatory region of another gene resulting in a fusion protein that gains aspects of both original proteins such as the DNA-binding domain of one and the protein-protein interaction domain of the other protein . As a coChromosomal rearrangements frequently act as strong drivers of myeloid leukemogenesis. In childhood and adolescent AML, structural chromosomal aberrations such as fusions and translocations are often the only genomic variants detected, whereas in adult AML patients short variants and combinations of several independent mutations are more common . TransloExemplified, we are describing in the next paragraph some of the most common chromosomal rearrangements for the various hematological malignancies. It is important to note that this list is by no means complete. Well-known AML-causing translocations are the fusion of the transcription factors AML1 and ETO , PML and RARα  as well as MLL and AF9 [t] . The t translocation resulting in the fusion protein BCR-ABL1, known as the Philadelphia chromosome  transloc. The fusIn recent years, other structural variations (SVs) than translocations have been discovered as an underlying or supporting mechanism for disease development and progression. These SVs include among others deletions, amplifications such as duplications, inversions, and single nucleotide polymorphisms (SNPs).Deletions of the 11q23 region affecting the ATM gene have been discovered to play a role in a number of hematological malignancies such as B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphomas (MCL) . InFurthermore, next-generation sequencing highlighted that around 2% of the genome contains protein-coding genes. Single nucleotide polymorphisms (SNPs) are inherited substitutions of a single nucleotide which might affect the protein-coding sequence and hence its function. In some cases the presence of SNPs in genes regulating DNA repair, metabolism or cell cycle increases the probability of cancer development . For exaTo identify novel SVs in cancer patients, there have been a number of studies analyzing the 3D genome structure , 36. Hi-How alterations to the 3D genome structure influence disease development and progression was also shown by the identification of the inversion between 3q21 and 3q26 , 38. Thiin situ hybridization) flow cytometry and SNP arrays are the best established techniques. PCR diagnostics is used to look for specific disease-causing genetic defects by amplifying specific target genes , FISH   leads to the constitutively active fusion protein BCR-ABL1 tyrosine kinase which transfers phosphate from ATP to tyrosine residues of various substrates and finally leads to massively increased proliferation and decrease of apoptosis in myeloid precursor cells via multiple downstream signaling pathways . Importa2 q34;q1. The tyr9/L equally benefit from a chemotherapy-free regimen has not been conclusively answered yet. Besides its role as a therapeutic target, PML-RARα serves as a biomarker specific to the disease. PCR-based techniques allow rapid diagnosis and measurement of residual disease (MRD) with distinct prognostic implications, as the absence of detectable transcripts is a precondition for long-term survival  encoding the PML-RARα fusion is the prevailing genomic abnormality and most often the only driver mutation in APL. Therapeutic doses of ATRA can stop the PML-RARα-mediated repression of target genes and release the differentiation block in promyelocytes , sometimsurvival .Classic Hodgkin's lymphomas include small numbers of malignant Reed-Sternberg cells within an extensive but ineffective inflammatory and immune cell infiltrate . One wayThe complementary mechanisms of PD-1 ligand overexpression in Hodgkin's lymphoma suggest that this disease may have genetically determined vulnerability to PD-1 blockade. Co-amplification of PDL1 and PDL2 on chromosome 9p24.1 suggests receptor rather than selective ligand blockade as a treatment strategy. The immune escape of malignant cells by upregulation of PDL1 and PDL2 can be at least partially abrogated with checkpoint immunotherapy. With the introduction of antibodies targeting the PD1 receptor on T-cells, the therapeutic outcome for Hodgkin lymphoma patients who relapsed after initial therapy has improved  66, 67), 6766, 6In addition to the standard therapeutic opportunities in hematological malignancies described above which are mainly targeting fusion proteins resulting from genetic translocations, novel drugs targeting the epigenome such as super enhancer blockers including BET and CDK7 inhibitors have recently been discovered and are reviewed elsewhere , 68. As Despite intensive research into the identification of specific SVs apart from translocations as well as into the understanding of the 3D genome structure of malignant cells, these findings could so far not be translated into the clinic and will be subject to further translational research. The application of curaxins, an anti-cancer agent that intercalates into DNA without inducing DNA damage, prevents looping of normally interacting DNA fragments due to the inability of CTCF to bind to its cognate binding sites which in turn affects the spatial genome structure and thus gene expression . This prMajor challenges regarding the detection of SVs are the prioritization of diagnostic tools for their identification, especially considering limited resources for applying advanced technologies. Moreover, as the presence of multiple targetable SVs in the same patient might offer various treatment approaches, new questions regarding the sequence of therapies become apparent.JS, JR, CK, and CE have drafted the review article and revisited it critically for important intellectual content and accurate citations. JS and CK have substantially contributed to the conception of the review article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


A), NMDA, and non-NMDA type glutamate receptors are brought together in a historical and conceptual framework. We extend the analysis toward a state-of-the art view of how neurosteroid modulation of neural circuitry function may affect memory and memory deficits. By aggregating the results from multiple laboratories using both animal models for disease and human clinical research on neuropsychiatric and age-related neurodegenerative disorders, elements of a circuitry level view begins to emerge. Lastly, the effects of both endogenously active and exogenously administered neurosteroids on neural networks across the life span of women and men point to a possible underlying pharmacological connectome by which these neuromodulators might act to modulate memory across diverse altered states of mind.Memory dysfunction is a symptomatic feature of many neurologic and neuropsychiatric disorders; however, the basic underlying mechanisms of memory and altered states of circuitry function associated with disorders of memory remain a vast unexplored territory. The initial discovery of endogenous neurosteroids triggered a quest to elucidate their role as neuromodulators in normal and diseased brain function. In this review, based on the perspective of our own research, the advances leading to the discovery of positive and negative neurosteroid allosteric modulators of GABA type-A (GABA A major question in neuroscience since the initial discovery that somatically released gut peptides could alter central nervous system (CNS) function relates to whether and how the body can influence or modulate brain function. The science of neuroendocrinology was advanced conceptually 50 years ago by the independent discoveries of Schally, Leeman and Reichlin, demonstrating that the gut peptides thyrotropin-releasing hormone (TRH) , 2 and sThe BBB does not impair access of sex steroids to the CNS to the same extent as gut peptides. Lipophilic steroid hormones, such as progesterone, estradiol and testosterone cross the BBB and readily gain access to the CNS  where thneurosteroids and an intensive search began to identify which steroids belonged to this group and to define their function. An early clue came from the research of Selye , a novel negatively charged steroid derived from the sulfation of pregnenolone (PREG), potentiated N-methyl-D-aspartate receptor (NMDAR) function  . From a Memory dysfunction seriously impacts performance of routine tasks necessary for a productive and healthy life, including the ability to maintain gainful employment and compliance with treatment plans . This reNeurosteroid synthesis involves translocation of cholesterol across the mitochondrial membrane by transport proteins, such as the steroidogenic acute regulatory protein (StAR protein), the translocator protein (TSPO), voltage-dependent anion channel (VDAC) protein and the adenine nucleotide transporter (ANT) protein –89. The The sulfation and desulfation of neurosteroids further alters both the pharmacokinetic and pharmacodynamic properties of these endogenous neuromodulators . In humaNeurosteroids and their sulfated conjugates can be characterized based on their core backbone structures as pregnanes, pregnenes, androstanes, progesterones, and deoxycorticosterones. Neurosteroids in these respective subcategories include: pregnanolone and pregnanolone sulfate; PREG and PregS; dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS); progesterone and ALLO; and, deoxycorticosterone and THDOC . While dThe physiologic effects of neurosteroids are mediated through direct interactions with neurotransmitter receptors and transporters, and indirectly via promotion of second-messenger signaling cascades , 99–103.ARs -dependent and non-canonical mechanism involving G-proteins  receptors . The synf NMDARs . PregS mf NMDARs . Low nanproteins  . Moreover, PregS modulates CICR, which is a key mediator of neuronal plasticity. PregS may affect CICR indirectly by activation of NMDARs or L-type voltage-gated Ca2+ channels (L-Type VGCCs) and not by direct activation of the Ca2+ release-activated Ca2+ channel protein 1 (ORAI1) or stromal interaction molecule 1 (STIM1).PregS increases spontaneous excitatory post-synaptic currents (sEPSC) frequency but not amplitude. This demonstrates PregS-mediated presynaptic regulation of spontaneous glutamate release and points to a potential significant impact of PregS on hippocampal function. Presynaptic transient receptor potential channel (TRP channel) receptor activation by PregS modulates glutamate release and increases sEPSC in acutely isolated hilar neurons of the dentate gyrus, an increase that is blocked by TRP channel antagonists . Dong et2+ currents and inhibits GABAAR-mediated chloride currents , progesterone and its metabolite ALLO is now relatively well-described. For instance, membrane-bound ER receptors, such as ERα localize at the cell surface where they regulate cell signaling mediated by ER produced in the CNS; this function is in addition to their well-recognized classical intracellular localizations where these receptors function to modulate transcription –166. IntXenopus oocytes, was demonstrated by Farb et al.  metabolism of the parent neurosteroid molecule and active metabolites may have a different mechanisms of action; (2) dosing schedules can be acute or chronic; and (3) pharmacokinetic and pharmacodynamic interactions between the neurosteroids and endogenous levels of circulating steroid hormones can fluctuate over time.Performance on tests of memory function also depends on when neurosteroids are administered in relationship to training or testing. For example, administration of neurosteroids before training can influence both acquisition and consolidation of new information, whereas administration after training is expected to influence consolidation and recall but not acquisition. The type of memory function being assessed  may also be more or less sensitive to the effects of neurosteroids. Finally, the age and cognitive status of the study subjects must be considered. Each of these factors is explored in greater detail below.Neurosteroids are metabolized to other neurosteroids that can also influence neurologic function. For example, PREG is a lipophilic precursor of ALLO, which is also a metabolite of progesterone. Administration of a loading dose of PREG is associated with an increase in serum ALLO levels . AlthougAdministration of 5α-reductase inhibitors, such as finasteride appears to prevent the metabolism of progesterone to ALLO and may thereby influence the neuromodulatory effects of endogenous as well as exogenous sources of these neurosteroids –195. StuAcute administration of ALLO improves memory function in one mouse model of AD , but othAR positive modulator ALLO to mice interferes with acquisition and consolidation on a hippocampal-dependent novel object recognition task  acquisition; (encoding); (2) consolidation; and (3) retrieval . As a result, in addition to their unique and sometimes complex mechanisms of action, the timing of neurosteroid administration can also influence performance on specific tests sensitive to the different aspects of learning and memory function. For example, post-acquisition administration of PregS is associated with improved retention in rodents on a passive avoidance paradigm, indicating that this positive modulator of glutamatergic neurotransmission facilitates consolidation . SystemiBut what about the specific type of memory function being assessed with a specific task; how might this affect interpretation of behavioral response to neurosteroids? Different types of memories require activation of different brain regions. Regional changes in activation are also associated with specific neuropsychiatric and neurologic disorders. Problems with attention, concentration, and motivation can interfere with encoding of new information and, thus, with performance on tests of memory function . While tThe role of neurosteroids in semantic memory function can only be effectively studied in humans who have the inherent ability to verbally express what they know about the world . Humans The effects of neurosteroids on learning and memory for fear-inducing stimuli appears to be different in males and females, who show different brain levels of ALLO at baseline as well. Augmenting levels of ALLO in the bed nucleus of the stria terminalis (BNST) of males, who have lower levels of ALLO at baseline, promotes contextual freezing. By contrast, reducing intra-BNST levels of ALLO in females, who have higher brain ALLO levels at baseline, enhances the expression of contextual freezing . In addide novo by Purkinje cells  imaging studies using the high-affinity sigma-1 (σ-1) receptor selective PET tracer [18F]1-(3-Fluoropropyl)-4-[4-cyanophenoxy) methyl]piperidine ([18F]FPS) as a radioligand suggest that neurosteroids including DHEA bind to σ-1 receptors in vivo . Sigma-1in vivo , 263. Agin vivo .in vivo (PET scans using the radiotracer [carbonyl-(11)C]WAY-100635 indicate that progesterone and DHEAS modulate serotonin 1A (5-HT1A) receptor binding in vivo , 266. Whin vivo , the rolHyperactivity of entorhinal cortical and hippocampal circuits are also thought to underlie neurodegenerative disorders, such as AD and mild cognitive impairment (MCI) –272. EarALLO may be useful in attenuating the hyperactivity implicated in early stage AD , 276. InN,N-dialkyl-2-phenylindol-3-ylglyoxylamides) that also show anxiolytic activity promote a reduction in oxidative stress and pro-inflammatory enzymes in glial cells via promotion of neurosteroid synthesis  both improves attention but also impairs declarative memory function , suggestThe BNST, which is also referred to as the extended amygdala, receives input from the hippocampus and shares reciprocal projections with the paraventricular nucleus of the thalamus , 293–296Selective serotonin reuptake inhibitors (SSRIs) increase brain levels of ALLO in humans and animals, suggesting that the anxiolytic effects of SSRIs may be related in part to their effect on CNS levels of this endogenous GABAergic modulator , 297–301When compared with normal subjects and patients with major depression, elderly patients with generalized anxiety disorder (GAD) show more deficits on tests of short-term memory function . The sevCortisol seems to enhance treatment outcomes in a small group  treated with exposure-based group therapy . In addiDHEA and DHEAS appear to counteract the negative effects of increased cortisol on working memory function in women and men, respectively , 316. A The response to stress appears to be influenced in part by circulating steroid hormones. Stress increases associative learning and dendritic spine density in the hippocampus of male rats, but impairs associative learning and reduces spine density in females . The potAnimal studies suggest that developmental exposure to ALLO influences subsequent responsivity to anxiolytics in adulthood , 330–332Restoration of altered endogenous neurosteroid levels via modulation of steroidogenesis mediated by pregnane xenobiotic receptors (PXR) and the endocannabinoid system has been suggested as an alternative to direct administration of neurosteroids , 337. BeARs , the primary chemical messenger implicated in the onset of puberty and sexual maturation . CentralARs , 340. AlARs .ARs, which are expressed at higher levels than normal in the CA1 region of the hippocampus during puberty. GABAARs of the α4β2δ subtype, which have a δ subunit instead of a γ subunit, play a role in tonic inhibition in areas, such as the dentate gyrus and cortex . In a study conducted by Brown et al. , 80 adulAR expression, in particular the α2 subunit, are known . GAD67 deficiencies together with changes in GABAre known –356. Hypre known , may inire known –364. Whare known . Disruptre known .ARs and sodium channels have been shown to enhance cognition  are elevated, suggesting a possible role for PregS in improvement of learning and memory function  is a neuromodulator and a key player in several neural disorders in which cognitive deficits are characteristic, such as schizophrenia, attention deficit hyperactivity disorder, and depression –381. Thesporters  is theresporters –385. Sevsporters . These msporters .2+-dependent manner , an orally bioavailable synthetic analog of ALLO, is a positive allosteric modulator of GABAfor PTSD , 390–392for PTSD , future for PTSD .2+]i)-dependent mechanism . These drawbacks are further exacerbated by the susceptibility of the essential 3-hydroxysulfate to hydrolysis by sulfatases. To overcome these limitations, we and others are using PregS analogs to decipher mechanistic aspects of PregS-mediated effects on learning and memory function. We recently reported that low nanomolar concentration of PregS induce a delayed-onset increase of the neuronal response to NMDA and trafficking of NMDAR to the cell surface through an intracellular ([Caechanism  (Figure currents  (Figurescurrents , 9. Morepharmacological connectome that reflects the interactions of neurosteroids with various neural networks involved with the encoding and recall of memories. We believe that a neural circuitry framework will help to guide future investigations into the potential role of neurosteroids and their synthetic analogs as neurotherapeutics for memory dysfunction (The effects of neurosteroids in memory function in neuropsychiatric and neurologic disorders reflect their modulatory interactions exerted via selective binding at the amino and transmembrane domains of specific subunits comprising GABA and glutamate receptors, among others. Age- and disease state-dependent changes in endogenous levels of neurosteroids appear to play a role in the emergence of the unique functional imbalances implicated in specific neuropsychiatric disorders and the associated memory deficits, which are mediated in part by changes in neural network activity within specific brain regions implicated in the encoding, consolidation, and retrieval of memories. It may be helpful to think of these findings in terms of a function .All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


For the last century or so, the mature, differentiated cells throughout the body have been regarded as largely inert with respect to their regenerative potential, yet recent research shows that they can become progenitor-like and re-enter the cell cycle. Indeed, we recently proposed that mature cells can become regenerative via a conserved set of molecular mechanisms , suggesting that a program for regeneration exists alongside programs for death (apoptosis) and division (mitosis). In two Reviews describing how emerging concepts of cellular plasticity are changing how the field views regeneration and tumorigenesis, we present the commonalities in the molecular and cellular features of plasticity at homeostasis and in response to injury in multiple organs. Here, in part 1, we discuss these advances in the stomach and pancreas. Understanding the extent of cell plasticity and uncovering its underlying mechanisms may help us refine important theories about the origin and progression of cancer, such as the cancer stem cell model, as well as the multi-hit model of tumorigenesis. Ultimately, we hope that the new concepts and perspectives on inherent cellular programs for regeneration and plasticity may open novel avenues for treating or preventing cancers. Summary: Epithelial cells in diverse tissues have an innate plasticity program  such that differentiated cells can become regenerative upon large-scale insults to an organ. Thus, the proliferating, regenerative cells in an organ may not always derive directly from stem cells, which invites us to refine theories about the cell of origin of cancer such as the multi-hit model of tumorigenesis. HRas, KRas and NRas are commonly mutated in human cancers  is lined by an epithelium that is flat on the luminal , which is mostly expressed in mature chief cells; basic helix-loop-helix family member A15 , which is almost exclusively expressed in chief cells; and leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5), which are likewise almost exclusively expressed in chief cells  and Mist1]  haploinsufficiency  , a clearof PDACs  and at tof PDACs . Geneticpancreas . Interespancreas  or specipancreas , a subseive KRAS . Althougnd PanIN , that isnd PanIN , additiond PanIN  or even ficiency   with respect to tumorigenesis in the pancreas carries some advantages over the stomach. The absence of SCs in the adult pancreas facilitates this, because increased proliferation during injury-induced regeneration must come from mature cells, whereas, in stomach and intestines, professional proliferating SC populations may also play a role in repair. Thus, studies of acinar cells are rapidly identifying the signaling pathways and genetic mechanisms governing the acinar cell changes, many of which will likely be shared in mechanisms of paligenosis across different organs  Fig. 3BBFig. 3B.Mist1─/─ mice or mice with defective MIST1 exhibit both abnormal acinar cell maturation and ADM response (Mist1 expression blocks ADM in spite of the presence of constitutively active KrasG12D (Similar to gastric chief cells, mature acinar cells express MIST1 to maintain their subcellular secretory architecture . Mist1─/response . Forced KrasG12D . Other tKrasG12D B; notablKrasG12D , myelocyKrasG12D  and KrupKrasG12D  promote KrasG12D , nuclearKrasG12D  and BHLHKrasG12D  drive thAs mentioned above, the process whereby acinar cells convert to ADM parallels the process of gastric chief cells becoming SPEM. Thus, the paligenosis program for conversion of mature cells to regenerative cells is generally similar with the same stepwise sequence of autodegradation, SOX9/metaplastic gene expression and cell cycle re-entry. Accordingly, inhibition of autophagy/lysosomes or mTORC1 activity blocks the progression to ADM as it blocks progression to SPEM in the stomach . We expeIn the search for the cell of origin for epithelial cancers, investigators have long favored stem and progenitor cells as the likely culprits, owing to their constitutive proliferative capacity and supposed longevity . HoweverOpportunities to inhibit tumor initiation at the cell of origin may arise in multiple tissues if common pathways can be identified and manipulated to block their dedifferentiation. As a start, we can look at the many similarities between the stomach and pancreas discussed in this Review. Both systems begin with large, long-lived secretory cells that undergo paligenosis to give rise to smaller, simpler cells reminiscent of embryonic cell types. Both systems also lose similar maturity markers and share many signal-transducing and metaplastic genes, and both involve a role for inflammation . Recent KRAS activation inhibits a paligenotic cell's ability to redifferentiate, which we describe as the cyclical hit model (Data from the stomach and pancreas support a model wherein mutations are acquired and stored through cycles of differentiation and dedifferentiation until a neoplastic mutation such as it model B. This mit model , with geit model . Metaplait model , consistit model , and theit model . It is tClearly, we are only at the beginning of understanding how cell plasticity plays a role in tumorigenesis and how tumors can adapt to chemotherapy and radiation therapy. We will explore more angles in part II of this Review , but exp