Invasive aspergillosis (IA) is a life-threatening fungal disease commonly diagnosed among individuals with immunological deficits, namely hematological patients undergoing chemotherapy or allogeneic hematopoietic stem cell transplantation. Vaccines are not available, and despite the improved diagnosis and antifungal therapy, the treatment of IA is associated with a poor outcome. Importantly, the risk of infection and its clinical outcome vary significantly even among patients with similar predisposing clinical factors and microbiological exposure. Recent insights into antifungal immunity have further highlighted the complexity of host-fungus interactions and the multiple pathogen-sensing systems activated to control infection. How to decode this information into clinical practice remains however, a challenging issue in medical mycology. Here, we address recent advances in our understanding of the host-fungus interaction and discuss the application of this knowledge in potential strategies with the aim of moving toward personalized diagnostics and treatment (theranostics) in immunocompromised patients. Ultimately, the integration of individual traits into a clinically applicable process to predict the risk and progression of disease, and the efficacy of antifungal prophylaxis and therapy, holds the promise of a pioneering innovation benefiting patients at risk of IA. Aspergillus with clinical manifestations that range from colonization to allergic bronchopulmonary aspergillosis and disseminated forms of infection  by resident macrophages, whereas neutrophils are instead proficient at handling hyphae germinating from conidia that escape macrophage surveillance through an array of extracellular killing mechanisms . This moInnate immune cells are equipped with pattern recognition receptors (PRRs) able to discriminate pathogen-associated molecular patterns PAMPs; . StimulaThe fungal cell wall is the main source of PAMPs owing to its dynamic composition and structural properties according to morphotype, growth stage and environmental conditions . Toll-liA. fumigatus is determined not only by the relative degree of stimulation of the individual PRRs but also by the level of receptor cooperation and cellular localization. Indeed, a sequential activation of distinct signal transduction pathways through the PRR adapters myeloid differentiation primary response 88 (MyD88) and caspase-associated recruitment domain 9 (CARD9) in the respiratory epithelium and hematopoietic compartment in response to infection was recently reported  inflammasome leading to the production of bioactive interleukin (IL)-1β -1β . Indeed, (IL)-1β . By prev (IL)-1β . Along t (IL)-1β .Soluble PRRs found in the fluids lining the epithelial surfaces support fungal sensing by binding to conidia and enhancing their uptake by phagocytes. Among these, the long pentraxin 3 (PTX3) was demonstrated to play a non-redundant role in antifungal host defense  by enhanA. fumigatus conidia restrains neutrophil infiltration and cytokine production  oxidase leading to a defective production of ROS and underlying CGD is the best known example of primary immunodeficiency associated with a distinctive predisposition to IA . PatientOur increasing ability to analyze human variability at the DNA level has made possible the identification of genetic factors implicated in the development of IA in hematological patients , providiTLR4 increasing risk of IA after HSCT was one of the first solid reports illustrating the remarkable influence of host genetics on the susceptibility to IA  that, by affecting production of A. fumigatus-induced proinflammatory cytokines by mononuclear cells, influenced susceptibility to mold infection after solid organ transplantation (A number of positive associations between genetic variants in cytokine and chemokine genes and vulnerability to IA has also been reported . One recantation .PTX3 associated with increased risk of IA in the corresponding HSCT recipient was found to compromise PTX3 expression during the developmental programming of neutrophils in the bone marrow, leading to a defective antifungal capacity of newly reconstituted neutrophils (A number of unconventional strategies have been employed to uncover additional candidate genes for susceptibility to IA . For exatrophils . Importatrophils . The factrophils  further trophils .Early diagnosis is crucial to a favorable outcome of IA. However, the existing diagnostic tools are often compromised by slowness, invasiveness, lack of standardization and insufficient understating of their kinetics . The intAlthough the interaction of the fungus with the immune system is being exploited to project novel and improved fungal diagnostics, efforts have on the other hand been also devoted to the implementation of clinical models aimed at the prediction of infection in high-risk patients. In this regard, interpretation of individual genomic, transcriptomic, proteomic or metabolomic profiles associated with impaired antifungal immune responses and their integration with clinical data is regarded as a promising approach Figure . Indeed,The discovery of accurate and reliable genetic markers of susceptibility may be a turning point toward innovative stratification strategies based on genetic screening or immune profiling to predict risk and severity of disease, efficacy of antifungal prophylaxis and therapy, and eventually contribute to the successful design of antifungal vaccines. As shown for PTX3 deficiency , targetiThe 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.


Dietary advanced glycation end-products (AGEs) form during heating and processing of food products and are widely prevalent in the modern Western diet. Recent systematic reviews indicate that consumption of dietary AGEs may promote inflammation, oxidative stress and insulin resistance. Experimental evidence indicates that dietary AGEs may also induce renal damage, however, this outcome has not been considered in previous systematic reviews. The purpose of this review was to examine the effect of consumption of a high AGE diet on biomarkers of chronic disease, including chronic kidney disease (CKD), in human randomized controlled trials (RCTs). Six databases  were searched for randomised controlled dietary trials that compared high AGE intake to low AGE intake in adults with and without obesity, diabetes or CKD. Twelve dietary AGE interventions were identified with a total of 293 participants. A high AGE diet increased circulating tumour necrosis factor-alpha and AGEs in all populations. A high AGE diet increased 8-isoprostanes in healthy adults, and vascular cell adhesion molecule-1 (VCAM-1) in patients with diabetes. Markers of CKD were not widely assessed. The evidence presented indicates that a high AGE diet may contribute to risk factors associated with chronic disease, such as inflammation and oxidative stress, however, due to a lack of high quality randomised trials, more research is required. Lifestyle factors, such as diets high in fat, sugar and salt, play a key role in the development and progression of chronic diseases, such as type 2 diabetes (T2DM), cardiovascular disease (CVD) and chronic kidney disease (CKD) . The modCurrent World Health Organisation dietary recommendations for the prevention of chronic disease recommend limiting the intake of free sugars, saturated fat and salt . At presThis systematic review was conducted in accordance with the preferred reporting items for systematic review and meta-analyses protocols (PRISMA-P) 2015 statement . StudiesIn total six databases were searched  in April 2015. The Cochrane library of clinical trials was also searched. The following keywords were used: (Concept 1)  AND (Concept 2) . No limits in terms of language or years were set on databases when searching. Subject headings were also searched in order to locate relevant studies that may not contain key words in the title or abstract. Reference lists of relevant original research and reviews articles were hand searched.Titles and abstracts of publications returned from the search were screened for relevance by one reviewer. Selected articles were retrieved and assessed for inclusion using the criteria described. Studies which could not be clearly included or excluded were screened by a second reviewer.Endnote was used to store and manage references for all studies returned for each database. Microsoft Excel was used to collate extracted data. All data were extracted by using a predefined data extraction template that was based on the National Health and Medical Research Council (NHMRC) of Australia data extraction template for RCTs and cohort studies.Data extraction variables included: affiliation/source of funding; study design ; study duration; location/setting; population size and characteristics including inclusion and exclusion criteria; dietary intervention details such as method of delivery, differences in AGE content, energy content and macronutrient composition; method of assessing AGE content of diet; method of randomisation; blinding; measurement and reporting of compliance to dietary intervention; medication and supplementation; and any additional risks of bias identified.c (HbA1c); CVD (oxidised low density lipoprotein (OxLDL)), vascular cell adhesion molecule-1 (VCAM-1) and intracellular cell adhesion molecule-1 (ICAM-1)); and CKD  and plasma Cystatin C). Secondary outcomes of interest were levels of circulating, urinary and faecal carboxymethyl lysine (CML) a well-characterised AGE.The primary outcomes of interest extracted from each study were differences in: biomarkers of inflammation , interleukin-6 (IL-6), C reactive protein (CRP) and monocyte chemoattractant protein-1 (MCP-1)); oxidative stress (8-isoprostane); T2DM (homeostatic model assessment insulin resistance (HOMA IR), fasting blood glucose (FBG), haemoglobin A1The Cochrane risk of bias tool  was usedd) in order to compare the results across the studies. A Cohen’s d of 0.2–0.3 was considered small; 0.5 medium; and 0.8 or greater as large. A negative sign indicates an adverse effect due to dietary intervention. For some studies it was not possible to calculate effect size due to pre and post-means or standard deviations not being reported.Data for each of the primary and secondary outcomes were synthesised and where possible reported as means at baseline and end of the intervention for each study group. This data was used to calculate the effect size  were included and therefore, the generalisability of these results are limited. In addition, the authors did not specify whether these patients suffered from comorbidities such as diabetes, which may have confounded results. Again, further higher-quality studies with larger samples sizes are required before a conclusion can be made about the association between a high AGE diet and oxidative stress in chronic conditions. Patients with T2DM are thought to have increased levels of oxidative stress, in particular, of circulating 8-isoprostanes, a marker of lipid peroxidation . HyperglAll of the studies that reported significant increases in circulating AGEs (measured as CML) in response to a high AGE diet were performed within the same research group ,23,24,25in vivo  in order to delineate the physiological mechanisms by which dietary AGEs might elicit their effects. Six studies across all populations observed parallel changes in serum AGEs and inflammatory and/or oxidative stress markers ,23,24,25c [Other than inflammatory factors, the studies performed to date suggest that a high AGE diet does not increase risk factors for T2DM in healthy or overweight individuals, patients with diabetes or patients with CKD. Dietary AGEs do not influence fasting blood glucose levels or HbA1c ,22,24,25c ,39,40. Ac  to indicc . The onlc  that repc ,22, it aThere is evidence to suggest high AGE diets promote risk factors for CVD in patients with diabetes ,24. VCAMThe majority of studies included in this review scored low in the quality analysis due to gaps in reporting and methodological flaws, thus limiting the strength of the findings from this review. Only one study reported a power calculation  althoughThe diversity of study populations further complicated the interpretation of this review. Medication use of participants with diabetes included statins ,24, metfThough there were several studies which measured the effect of a high AGE diet on markers of inflammation and oxidative stress, and serum AGEs, due to differences in the way the results were reported and also missing n values for intervention groups in one study , it was Some studies reported use of vitamin supplements ,24 whileDietary intake was poorly reported in several articles ,21,22,25The majority of studies relied on a published AGE database  to deterFinally, the included studies had relatively short follow up duration (two to 16-weeks). The adverse consequences of a high AGE diet may arise over a period of years rather than weeks or months as AGEs accumulate, glycate other proteins, or are incorporated into tissues. Therefore, studies of longer duration are required.The risk of bias assessment tool used in this review used may have resulted in higher risk of bias or poorer quality ranking being assigned to studies that were more transparent with reporting. Also, limitation of the included studies to isocaloric diets resulted in the exclusion of one relevant and well reported trial . Finallyet al. [The conclusions drawn about the lack of high quality long-term trials in this field agree with previously published systematic reviews ,3 despitet al. . Anotheret al. . The oveThe findings of this review suggest that consumption of a high AGE diet increases circulating levels of TNFα and AGEs in healthy individuals and in individuals with chronic disease. Furthermore, there is evidence to suggest that dietary AGEs promote oxidative stress in healthy adults, and increase CVD markers in patients with diabetes. As such, dietary AGEs may play a role in the promotion of chronic conditions such as T2DM, CVD and CKD through increasing oxidative stress and inflammation.The limitations of the current evidence, highlighted in this review, indicate that further high quality randomised controlled trials are required to fully delineate the adverse consequences of a high AGE diet in both healthy people and in patients with diabetes and CKD before any dietary recommendations can be made. Future studies into the effect of a high AGE diet, or benefit of a low AGE diet need to: (i) control for confounding factors (such as fat content or heat sensitive vitamins) between study diets; (ii) use validated methods to assess the AGE content of foods in the diet; (iii) provide participants with meals to increase compliance; (iv) include justifications of sample size; (v) include biomarkers of kidney function as primary outcomes; (vi) include methods to assess the metabolism of dietary AGEs in order to better elucidate the mechanisms by which a high AGE diet may have an adverse effect. Given that the standard Western diet contains a high amount of AGEs, further research into the consequences of habitual high AGE diets is important. The potential benefits of restricted AGE intake are promising and could offer a simple dietary therapy in the prevention and treatment of chronic conditions.


Nol11 is strongly expressed in the developing cranial neural crest (CNC) of both amphibians and mammals, and knockdown of Xenopus nol11 results in impaired pre-rRNA transcription and processing, increased apoptosis, and abnormal development of the craniofacial cartilages. Inhibition of p53 rescues this skeletal phenotype, but not the underlying ribosome biogenesis defect, demonstrating an evolutionarily conserved control mechanism through which ribosome-impaired craniofacial cells are removed. Excessive activation of this mechanism impairs craniofacial development. Together, our findings reveal a novel requirement for Nol11 in craniofacial development, present the first frog model of a ribosomopathy, and provide further insight into the clinically important relationship between specific ribosome biogenesis proteins and craniofacial cell survival.The production of ribosomes is ubiquitous and fundamental to life. As such, it is surprising that defects in ribosome biogenesis underlie a growing number of symptomatically distinct inherited disorders, collectively called ribosomopathies. We previously determined that the nucleolar protein, NOL11, is essential for optimal pre-rRNA transcription and processing in human tissue culture cells. However, the role of NOL11 in the development of a multicellular organism remains unknown. Here, we reveal a critical function for NOL11 in vertebrate ribosome biogenesis and craniofacial development.  nol11 is strongly associated with the developing head in vertebrates and that insufficient Nol11 results in striking malformations of the craniofacial skeleton. We further show that reduced Nol11 impairs critical early steps in ribosome production, which triggers apoptosis within cell populations that contribute to the head. Increased cell death is at least partially the cause of the Nol11 craniofacial defect; reducing cell death rescues some of the craniofacial phenotype but not the ribosome biogenesis defect. In summary, we demonstrate for the first time that Nol11 is required for normal development of the vertebrate head and provide novel insight into the intriguing tissue proclivity of ribosomopathies.All cells require ribosomes, the cellular factories that produce proteins. A host of factors combine to produce the multiple complex units of a ribosome, many of which are still not well understood. Surprisingly, despite the ubiquitous requirement for ribosomes, defects in various ribosome biogenesis factors cause distinct and tissue specific phenotypes, collectively known as ribosomopathies. We examined the role of one ribosome biogenesis factor, Nol11, during embryonic development to determine if it too had a tissue specific phenotype. Here we show that expression of  The synthesis of ribosomes, the protein-manufacturing entities in cells, is fundamental to all of life. Therefore, it is surprising that defects in ribosome synthesis are compatible with the development of a multicellular organism, albeit with substantial morbidity. Several diseases of ribosome biogenesis, so-called ribosomopathies, have been described with a strikingly heterogeneous collection of symptomatologies –16. The An emerging class of ribosomopathies includes craniofacial anomalies. Craniofacial malformations are associated with over 700 human congenital syndromes, and the molecular causes of many of these diseases remain unknown . Often tInvestigations into the surprising relationship between craniofacial disease and defects in ribosome biogenesis are beginning to emerge. Defects in CNC derived craniofacial structures are associated with the ribosomopathy known as Treacher-Collins Syndrome ,15,16,21Ribosome biogenesis begins with the assembly of the nucleolus around ribosomal DNA (rDNA) repeats and with the transcription of the polycistronic pre-ribosomal RNA (rRNA) precursor that contains the sequences for the 18S, 5.8S and 28S rRNAs by RNA polymerase I (RNAPI). Over 200 ribosome biogenesis factors then process these rRNAs through a complex series of cleavages and modifications to assemble into the mature small 40S) and large (60S) subunits of the ribosome by incorporating 80 ribosomal proteins and the 5S rRNA –38. MatuS and larWe recently discovered the human analog of yeast Utp8 to be NOL11, a metazoan-specific nucleolar protein ,45. NOL1Xenopus tropicalis to investigate its role in vertebrate development. We report that nol11 mRNA expression is strongly associated with the developing CNC in both amphibians and mice. We further demonstrate that nol11 is required for optimal pre-rRNA transcription and pre-rRNA processing in Xenopus, and that nol11 knockdown results in activation of the nucleolar stress response, p53 stabilization, and a dramatic craniofacial phenotype. Importantly, the craniofacial defect can be partially rescued by p53 depletion, while the underlying transcriptional defect cannot, demonstrating that the pathology is due to the cellular response to impaired ribosome biogenesis. Together, our findings reveal a novel requirement for Nol11 in craniofacial development and provide further insight into the evolutionarily conserved relationship between specific ribosome biogenesis factors and the control mechanisms that regulate CNC survival and development.Here, we used the frog nol11 mRNA expression during vertebrate embryonic development. Intriguingly, despite the ubiquitous need for ribosomes, in situ hybridization of labelled anti-sense probes revealed robust, tissue specific expression of nol11 mRNA in both the frog and mouse. In Xenopus, transcripts are detected throughout the forming neural tube, and signal is particularly strong in anterior regions, from which the CNC form, at stages 14–16 (nol11 expression and CNC development is maintained at later stages of development (stages 22–36), where signal marks the CNC streams as they migrate into the facial primordia and differentiate. During these stages, expression in the neural tube becomes more restricted and is detected in regions of the hindbrain, isthmus and tail. Additional stage specific expression is lightly detected in the optic and otic placodes, the ventral blood islands, and diffusely in the presumptive splenic mesenchyme , the mandibular and maxillary portions of the first branchial arch (mdBA1 and mxBA1) and the more posterior BA. Interestingly, in both mice and frogs, Nol11 expression appears enriched in distal regions of the branchial arches at later stages of development  mediated knockdown in Xenopus tropicalis. In Xenopus, MOs can be injected at the one cell stage targeting the entire embryo or at the two-cell stage where embryos targeted to either just the right or left side can be selected. To test the efficacy of our knockdown, we examined Nol11 protein levels in uninjected controls (UC) and nol11 morphants by western blot, and confirmed a dose dependent impact on Nol11 protein levels during development  of treated embryos, while control MO (CMO) injected embryos were unaltered , as well as CNC patterning genes including gsc, dlx5, twist, dlx2 and xnot  in the pre-rRNA using a BLAST search. Aligning X. laevis and X. borealis pre-rRNA sequences, we identified two X. tropicalis Xentr7.1 scaffolds (xenbase.org). Scaffold sequence 169 contained sequences similar to X. laevis 5’ETS, 18S rRNA, internal transcribed spacer 1 (ITS1), and the 5’ portion of the 5.8S rRNA while scaffold 2385 only contained sequence similar to the 5’ portion of the 5’ETS  (TIF)Click here for additional data file.


During neural development, billions of neurons differentiate, polarize, migrate and form synapses in a precisely choreographed sequence. These precise developmental events are accompanied by discreet transitions in cellular polarity. While radial glial neural stem cells are highly polarized, transiently amplifying neural progenitors are less polarized after delaminating from their parental stem cell. Moreover, preceding their radial migration to a final laminar position neural progenitors re-adopt a polarized morphology before they embarking on their journey along a glial guide to the destination where they will fully mature. In this review, we will compare and contrast the key polarity transitions of cells derived from a neuroepithelium to the well-characterized polarity transitions that occur in true epithelia. We will highlight recent advances in the field that shows that neuronal progenitor delamination from germinal zone (GZ) niche shares similarities to an epithelial-mesenchymal transition. Moreover, studies in the cerebellum suggest the acquisition of radial migration and polarity in transiently amplifying neural progenitors share similarities to mesenchymal-epithelial transitions. Where applicable, we will compare and contrast the precise molecular mechanisms used by epithelial cells and neuronal progenitors to control plasticity in cell polarity during their distinct developmental programs. The developing central nervous system, including the spinal cord, retina and brain, occupies a complex developmental landscape wherein neural stem cells are born and then proliferate, differentiate and migrate long distances to form intricate networks, all of which ensure proper CNS functioning. Notably, almost all of the diverse cell types comprising the CNS originate from the neuroepithelium lining the embryonic neural tube and neural plate. Self-renewing multipotent cells  orient themselves along the apical-basal axis in a single layer, conferring a highly polarized structure on this germinal niche. Subsequent symmetric and asymmetric division of the neural stem cells imparts a pseudostratified appearance to neuroepithelium, in which the nuclei undergo interkinetic nuclear migration while the apical-basal surfaces of the cells remain anchored through intercellular junctions Figure . AlteratDevelopment of the neocortex, with its unique lamination process, provides an attractive model to investigate the cellular remodeling essential for establishing the CNS Rakic, , 2009. NUltrastructure studies show that like epithelial cells, newly formed RGCs are morphologically polarized  of the spinal cord. Spinal cord development is a multistage process with distinct subtypes V0, V1, V2, V3, interneurons and MNs Figure . ConvergBesides transcriptional control of adhesion proteins, delamination of progenitors also involves a change in polarity and cellular architecture, recently addressed in a new light by Das and Storey. By using structured illumination microscopy in chick neural tube, they discovered a cellular mechanism called apical abscission that participates in actin-myosin–dependent remodeling of primary cilium  complex comprising Pard3, Pard6, aPKC and cdc42 and crumbs-homologue (CRB) comprising Crb1-3, Pals1/MPP5 and Patj  and Purkinje cells) and minority interneuronal populations (Roussel and Hatten, in vitro and ex vivo, disrupts the actomyosin cytoskeleton and blocks radial migration of CGNs (Solecki et al., The maturation of CGNs and their migration requires polarization, which was carefully examined in two studies delineating role of Par complex in this process. The first study showed that manipulation of Pard6α function, both Addressing the morphological changes observed in newly born neurons and its relevance in setting up the laminar structure of CNS raises some interesting questions. How the polar plasticity of newly born is regulated and what are the key factors that are involved in this process across the various developing CNS structures? Further in the developing cerebellum, how do the neurons born from the RGCs after adopting a multipolar migratory feature upon reaching the second GZ restore their polarity? Like the epithelial system is there a regulator whose expression temporally coincides with the CGNs reacquiring epithelial characteristics aka MET like processes. If so, what would be some of the targets of this MET like processes in developing neurons? Do these factors also play a role in differentiation and maturation of the neurons?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.


Genes required for an organism to develop to maturity (for which no other gene can compensate) are considered essential. The continuing functional annotation of the mouse genome has enabled the identification of many essential genes required for specific developmental processes including cardiac development. Patterns are now emerging regarding the functional nature of genes required at specific points throughout gestation. Essential genes required for development beyond cardiac progenitor cell migration and induction include a small and functionally homogenous group encoding transcription factors, ligands and receptors. Actions of core cardiogenic transcription factors from the Gata, Nkx, Mef, Hand, and Tbx families trigger a marked expansion in the functional diversity of essential genes from midgestation onwards. As the embryo grows in size and complexity, genes required to maintain a functional heartbeat and to provide muscular strength and regulate blood flow are well represented. These essential genes regulate further specialization and polarization of cell types along with proliferative, migratory, adhesive, contractile, and structural processes. The identification of patterns regarding the functional nature of essential genes across numerous developmental systems may aid prediction of further essential genes and those important to development and/or progression of disease. genesis 52:713–737, 2014. The tools available to modern molecular biologists have rendered the removal of genes a systematic process as reflected by the current availability of increasing numbers of targeted deletions and conditional alleles  6.5–7.5, cardiac progenitors from the anterior mesodermal primitive streak migrate anteriorly and laterally on either side of the embryonic midline A   transcription factor et al., et al., Bmp2 null mutant mice experience embryonic lethality between E7.0 and E10.5 with severely delayed, ectopic or absence of cardiac development  predominantly promote cardiac specification in the PHF. The specifics of BMP signal transduction have been considered in greater detail elsewhere   function is also required for cardiac development. et al., LacZ transgene expression under Fgf10 promoter control in mice revealed contributions of a second heart field (SHF) to the outflow tract (OFT) myocardium, with transgene expression originating in the pharyngeal mesoderm from E7.5  is vital to SHF migration, survival, and differentiation. Mice null for Isl1 display absence of SHF derived structures (OFT and right ventricle) and have severely reduced atrial tissue  and bulboventricular groove, absence of endocardial cushions (ECCs) and absence of the proepicardium  genes are among the earliest differentially expressed genes during cardiac development. The Hand1 and Hand2 bHLH family transcription factors are both uniformly expressed in mice at E7.75 during the cardiac crescent stage of heart development before becoming restricted to left and right ventricles, respectively, during and after cardiac looping  demonstrated cardiac defects including defective looping and failure to establish distinct atria and ventricles and lack of trabeculation  and cyclin-dependent kinase 4 (Cdk4), which prevents cell cycle exit  transcription factors represent a group of at least 18 transcription factors that have diverse roles in cardiac development. Regarding chamber development, Tbx5 plays important roles in regulating an atrial-specific transcriptional program. During development, Tbx2 is essential during cardiac development with respect to nonchamber structures. Tbx2 is expressed in the AVC and atrioventricular cushions, OFT and inflow tract in the linear and looping heart before gradually decreasing to background levels by E15.0. In these regions, Tbx2 is thought to repress chamber-specific gene expression such as Nppa, Smpx, Cx40, and Slit3 allowing these areas to remain as primary myocardium for purposes of chamber alignment and to form specialist structures of ECCs, valves, septa, and conduction system components  initiate cascades in response to mechanical force, controlling heart rate, and force of contraction. This response can be desensitized by agonists binding to GPCRs resulting in their subsequent phosphorylation by GPCR kinases  migrate from the dorsal neural tube between the midotic placode and the caudal boundary of the third somite into the pharyngeal arches and OFT where they eventually form part of the OFT septum  thought to cause degradation of Titin causes embryonic lethality at ∼E9.0 due to defective sarcomeric formation , is essential for sarcomere assembly (Seguchi In contrast to the transcriptional and signaling pathways that direct many of the events of cardiac development, the functions encoded by genes lethally and exclusively disrupting sacromere function do not show much overlap with other groups of cardiac essential genes. From midgestation, the mammalian embryo requires cardiac contractility to pump blood throughout the cardiovascular system, delivering nutrients to embryonic cells. Impaired cardiac function as a result of disordered or functionally incomplete contractile apparatus assembly leads to embryonic lethality. Structural proteins that allow myofilament assembly and function are required within the sarcomere to form the contractile units of the developing heart. The specific mechanical and structural role of sarcomere proteins makes it unsurprising that there is a functionally distinct group of genes displaying essentiality during sarcomere assembly, which are not involved in other aspects of cardiac development.et al., et al., et al., et al., et al., et al., Complete functional annotation of mammalian genomes is beginning to appear as a realistic possibility (Dolgin, et al., Efforts to functionally annotate the mammalian genome have increased the identification of essential genes. Recent experimental studies support the prediction that approximately 40% of mammalian genes are essential (White


The common carp is an important aquaculture species that is widely distributed across the world. During the long history of carp domestication, numerous carp strains with diverse skin colors have been established. Skin color is used as a visual criterion to determine the market value of carp. However, the genetic basis of common carp skin color has not been extensively studied.TYRP1, SILV, ASIP and xCT, showed significant differences in their expression patterns between the two strains.In this study, we performed Illumina sequencing on two common carp strains: the reddish Xingguo red carp and the brownish-black Yellow River carp. A total of 435,348,868 reads were generated, resulting in 198,781 assembled contigs that were used as reference sequences. Comparisons of skin transcriptome files revealed 2,012 unigenes with significantly different expression in the two common carp strains, including 874 genes that were up-regulated in Xingguo red carp and 1,138 genes that were up-regulated in Yellow River carp. The expression patterns of 20 randomly selected differentially expressed genes were validated using quantitative RT-PCR. Gene pathway analysis of the differentially expressed genes indicated that melanin biosynthesis, along with the Wnt and MAPK signaling pathways, is highly likely to affect the skin pigmentation process. Several key genes involved in the skin pigmentation process, including In this study, we conducted a comparative transcriptome analysis of Xingguo red carp and Yellow River carp skins, and we detected key genes involved in the common carp skin pigmentation process. We propose that common carp skin pigmentation depends upon at least three pathways. Understanding fish skin color genetics will facilitate future molecular selection of the fish skin colors with high market values. Coloration is one of the most diverse phenotypic traits in vertebrates, and it exerts multiple adaptive functions, such as species identification, camouflage, warning or threatening of predators, photoprotection, thermoregulation and photoreception matp, oca4, sox10, kit, ednrb, slc24a5 and many others, through collecting and identifying the pigmentation mutations In humans and mammals, the pigment melanin is the primary determinant of skin color. The availability of the complete human genome sequence and of adequate genomic resources, along with genome-wide association studies (GWAS), has provided insight into the genetic basis of the pigmentation process. In contrast to mammals, which possess only one type of pigment cell (the melanocyte), and amphibians and reptiles, which possess xanthophores, erythrophores and reflecting iridophores, teleost fish possess up to six different pigment cells, including melanophores, xanthophores, erythrophores, iridophores, leucophores and cyanophores Cyprinus carpio), a freshwater fish that is especially widespread in Europe and Asia, was domesticated more than 2,000 years ago. Over its long history of domestication, the common carp has been introduced into various environments worldwide, resulting in hundreds of strains or varieties that display rich biodiversity, genetic polymorphisms and diverse skin colors. Skin color is an important economic trait for common carp, as it acts as an important criterion for visually determining quality and market value. Several studies have provided initial insights into the genetic basis of skin coloration in common carp. For instance, David et al. reported that the MC1R gene was associated with the development of black pigmentation in the ornamental Koi common carp The common carp  and the Yellow River carp  are two traditional domestic strains of common carp in China. XGC, a regional strain from Xingguo County in the Jiangxi Province in Southern China, is known for its red color and has approximately 1,300 years of cultural history The Xingguo red carp  database, the UniProt database and the Ensembl zebrafish protein database, with an E-value cutoff of 1eectively . CumulatGene ontology (GO) annotation was then performed with these 73,928 unique gene-containing contigs using Blast2GO Based on the criteria that |fold-change|≧2 and p-value≦0.05, a total of 4,367 of the 198,781 assembled contigs showed significantly different expression in XGC skin compared with YRC skin. Differentially expressed contigs represented 2,012 unique genes, of which 874 genes were up-regulated in XGC and 1,138 genes were down-regulated . To valiTYRP1), premelanosome protein (SILV/PMEL), cysteine/glutamate transporter (xCT/SLC7a11) and agouti signaling protein (ASIP). Melanin is the major pigment present in vertebrates TYRP1 was 5.7-fold up-regulated in YRC skin compared with XGC, suggesting that TYRP1 is one key gene that contributes to brownish-black coloring in common carp by acting in the eumelanin synthesis pathway. TYRP1 is expressed specifically in melanocytes, and it plays a crucial role in pigmentation and color patterning by affecting melanin synthesis, stabilizing tyrosinase protein, modulating tyrosinase catalytic activity, maintaining melanosome structure, and affecting melanocyte proliferation and cell death TYRP1 was the first cloned pigmentation gene, and it was later mapped to the brown locus in mouse TYRP1 result in failure to form a black coat color, as observed in mouse TYRP1 is only detectable in cells containing eumelanin TYRP1 gene in eumelanogenesis. Similar roles for TYRP1 have been reported in teleost fish. Knockdown of the TYRP1 gene in zebrafish and medaka revealed that black eumelanin formation essentially relies on the presence of TYRP1TYRP1 in the skin coloration of the common carp.After carefully investigating the differentially expressed gene list from the skin tissues of XGC and YRC, we identified many putative pigmentation genes that may be associated with melanin synthesis, such as those encoding tyrosinase-related protein 1 , suggesting a significant effect on the production of pheomelanin in common carp. The functions of ASIP and xCT in pheomelanin synthesis have been widely studied in other species. ASIP can regulate pigmentation by antagonizing the binding of a-MSH to Mc1r, thus switching melanin synthesis from eumelanin to pheomelanin TYRP1, DCT, and TYR to inhibit the synthesis of eumelanin ASIP gene expression is up-regulated while TYRP1 gene expression is down-regulated in XGC skin. The important role of ASIP in determining skin or coat color has been demonstrated in human xCT (SLC7a11), a cysteine/glutamate exchanger, mediates the cellular uptake of cysteine xCT directly affects the pheomelanin synthesis pathway xCT expression caused marked inhibition of pheomelanogenesis xCT contributed to the production of pheomelanin, as indicated by our results.Several other genes in our differentially expressed gene list are involved in the production of pheomelanin, the most significant of which are  results , both ASnd GO level that were enriched in XGC skin relative to YRC skin. The top 10 of these are shown in We attempted to categorize the 2,012 differentially expressed genes based on their likely functions by using gene annotation, GO term enrichment analysis, and KEGG pathway analysis. Using the Blast2GO software, all the differentially expressed genes were classified into different cellular, biological and functional gene ontologies. Together with the GO annotation of the reference sequences, the web-based program WEGO As described in a pathway analysis of non-model fish species Tyr, DCT, TYRP1 and SILVMelanin biogenesis is under complex controls by multiple agents via pathways. Slominski et al. WNT5B, a member of the Wnt protein family, is expressed in pigment cells located at the extended posterior edges of the caudal fin in zebrafish WNT5B was 2.5-fold up-regulated in YRC, suggesting that WNT5B may be involved in the skin pigmentation process. SFRP5 (secreted frizzled-related protein 5), a member of the SFRP family that modulates Wnt signaling transduction, is highly expressed in the retinal pigment epithelium SFRP5 is higher in the skin of brownish-black YRC than in red XGC  and short reads (length below 30 bp) using CLC Genomics Workbench . The Trinity software was then used to assemble all of the cleaned reads using default parameters. The assembled sequences were then filtered using the CD-hit program to reduce redundancy. The resulting contigs that were larger than 200 bp were considered as the final non-redundant transcripts and were used as the reference sequences.−10. Gene ontology was performed by importing the zebrafish Blast results into Blast2GO software. GO terms were then assigned to each sequence automatically. The annotation output was categorized by cellular component, molecular function and biological process.The assembled reference sequences were used as query sequences to search against the NCBI nr database, the UniProt database and the Ensembl zebrafish protein database. Searches were conducted using the BlastX program with an E-value cutoff of 1eClean reads from the skin tissues of each common carp strain were first aligned to their respective reference sequences using Bowtie 2 A total of 20 genes with significantly different expression in the two carp strains were selected for validation using qRT-PCR analysis. The house-keeping gene β-actin was used as an internal reference. All primer sequences are listed in The web-based program WEGO was used with default parameters for statistical analysis of GO term overrepresentation among the genes with differential expression in the skin of the two carp strains. The study set represented the frequency of GO terms in the differentially expressed genes, while the population set corresponded to the whole reference gene set.To better understand the genetic mechanisms of skin color variation in common carp, we conducted a comparative analysis of the skin transcriptomes from two common carp strains with distinct skin colors, the red XGC and the brownish-black YRC. We detected 2,012 unique genes that were differentially expressed in the two strains. Further annotation, GO enrichment and pathway analysis indicated that key pigmentation-related genes were involved in at least three pathways that regulate pigment synthesis in the two strains. These results provide us with a valuable basis for understanding of the molecular mechanisms of skin pigmentation in teleost fish. Such understanding will facilitate the genetic selection and breeding of common carp with market-favored colors.Table S1Detailed information of the differentially expressed genes. The fold change cutoff is 2, and p-value cutoff is 0.05.(XLSX)Click here for additional data file.Table S2Primers used for qRT-PCR validation.(XLSX)Click here for additional data file.


It is now evident that elevated circulating levels of triglycerides in the non-fasting state, a marker for triglyceride (TG)-rich remnant particles, are associated with increased risk of premature cardiovascular disease (CVD). Recent findings from basic and clinical studies have begun to elucidate the mechanisms that contribute to the atherogenicity of these apoB-containing particles. Here, we review current knowledge of the formation, intravascular remodelling and catabolism of TG-rich lipoproteins and highlight (i) the pivotal players involved in this process, including lipoprotein lipase, glycosylphosphatidylinositol HDL binding protein 1 (GPIHBP1), apolipoprotein (apo) C-II, apoC-III, angiopoietin-like protein (ANGPTL) 3, 4 and 8, apoA-V and cholesteryl ester transfer protein; (ii) key determinants of triglyceride (TG) levels and notably rates of production of very-low-density lipoprotein 1 (VLDL1) particles; and (iii) the mechanisms which underlie the atherogenicity of remnant particles. Finally, we emphasise the polygenic nature of moderate hypertriglyceridemia and briefly discuss modalities for its clinical management. Several new therapeutic strategies to attenuate hypertriglyceridemia have appeared recently, among which those targeted to apoC-III appear to hold considerable promise. Whether plasma triglycerides, or more specifically, the lipoprotein particles in which they are transported between sites of absorption, lipolysis and remodelling and catabolism constitute an independent risk factor for CVD has been the subject of debate for decades . SignifiHypertriglyceridemia is generally defined and diagnosed as fasting plasma TG > 1.7 mmol/L or >150 mg/dL and is the consequence of environmental, behavioural and genetic factors, among which lifestyle is prominent  ••. SeverTriglycerides represent the transport module for fatty acids which provide an essential source of energy upon oxidation in mitochondria. A major source of TG is derived from dietary fat consumption. Dietary TGs are transported in intestinally derived apolipoprotein (apo) B48-containing chylomicrons, which enter the systemic circulation through the lymphatic system and target the heart as the first organ for delivery of fatty acids to fulfil energy requirements. The liver plays a cental role in TG homeostasis and maintains a steady state between TG synthesis, secretion and oxidation. In contrast to adipose tissue, the liver does not serve as an organ for TG storage under normal physiologic conditions. The liver can take up fatty acids derived from lipolysis in adipose tissue or from circulating lipoproteins but may equally synthesise fatty acids from carbohydrates in the process of de novo lipogenesis. In the liver, fatty acids can be partly stored as TG in lipid droplets or oxidised to generate energy in mitochondria in the process of beta-oxidation or packaged in apo B100-containing VLDL particles and secreted into the systemic circulation where they serve as a source for energy for peripheral tissues. The molecular pathway involved in the packaging of TG into both chylomicron and VLDL particles is remarkably similar, involving microsomal triglyceride transfer protein (MTTP) as described in detail elsewhere , 16.Triglycerides cannot pass through cell membranes freely. Consequently, intravascular lipolysis is an essential process for release of free fatty acids, which can then be taken up via specific fatty acid transporters or other yet unknown mechanisms. The underlying mechanism is still only partly understood, but identification of some of the key proteins involved has allowed progress in our understanding. Lipoprotein lipase (LPL) is the key enzyme which drives TG hydrolysis along the luminal surface of capillaries, whereas the recently identified protein glycosylphosphatidylinositol HDL binding protein 1 (GPIHBP1) provides the platform to allow lipolysis to occur at the endothelial cell surface , 18. LipAPOC2 have severe hypertriglyceridemia similar to LPL deficiency . Th. Th72]. For many years, accumulation of chylomicron and chylomicron remnants in plasma was believed to be the essential cause of postprandial hypertriglyceridemia , 83. HowInterestingly, the importance of postprandial lipoproteins in the development of atherosclerotic vascular disease was initially proposed almost 70 years ago by Moreton who wrote “the lipid particles must be assumed to be retained and deposited from the plasma-derived nutrient lymph stream which normally passes from the lumen through the intramural structures towards the adventitial venules and lymphatics. It may be theorised that the increased particle size of the lipids in sustained or alimentary hyperlipemia is the stimulus to the phagocytosis in the intima by macrophages and the formation of the typical foam cells” , 89. It As discussed above, recent epidemiological studies have unequivocally demonstrated that elevated levels of postprandial TG and remnant particles are clinically significant risk factors for CVD , 3, 6•. Following exclusion of secondary causes, treatment of mild to moderate hypertriglyceridemia should follow guideline recommendations, the initial step involving counselling on dietary habits, smoking and exercise . The objAPOC3 was discovered in 2008 in the Amish community in the USA and found to provide apparent cardioprotection [APOC3 are associated with low TG levels and reduced risk of ischemic heart disease in two general population studies involving more than 75,000 participants [New therapeutic options are currently under development that have been based on genetic evidence for reduced cardiovascular risk in families with phenotypes involving markedly diminished TG levels and rare causative monogenic mutations. Of the candidate proteins involved, apoC-III stands out as an elegant example. Indeed, a null mutation in human otection . Abundanicipants . Similaricipants .As discussed above, apoC-III is a key factor on the surface of TRL and is a critical modulator of the lipolytic activity of lipoprotein lipase. Circulating levels of apoC-III are elevated however and of the order of 10–20 mg/dL, suggesting that hepatic production of apoC-III may be more viable as a target compared to a monoclonal antibody approach to remove apoC-III protein, allowing maintenance of low plasma levels over extended periods of time . It is iThe number of patients with hypertriglyceridemia will grow significantly over the coming years, partly due to the increase in patients with diabetes mellitus type 2 and metabolic syndrome. Indeed, hypertriglyceridemia poses a major emerging challenge for public health and requires adequate targeting. As current therapies are not optimal for normalisation of elevated TG levels, the development of novel therapeutic agents is therefore warranted.


Marijuana is the most widely used illicit drug among adolescents and young adults. Unique cognitive, emotional, and social changes occur during this critical period of development from childhood into adulthood. The adolescent brain is in a state of transition and differs from the adult brain with respect to both anatomy  and neurochemistry . These changes are thought to support the emergence of adult cerebral processes and behaviors. The endocannabinoid system plays an important role in development by acting on synaptic plasticity, neuronal cell proliferation, migration, and differentiation. Delta-9-tetrahydrocanabinol (THC), the principal psychoactive component in marijuana, acts as a partial agonist of the cannabinoid type 1 receptor (CB1R). Thus, over-activation of the endocannabinoid system by chronic exposure to CB1R agonists  during adolescence can dramatically alter brain maturation and cause long-lasting neurobiological changes that ultimately affect the function and behavior of the adult brain. Indeed, emerging evidence from both human and animal studies demonstrates that early-onset marijuana use has long-lasting consequences on cognition; moreover, in humans, this use is associated with a two-fold increase in the risk of developing a psychotic disorder. Here, we review the relationship between cannabinoid exposure during adolescence and the increased risk of neuropsychiatric disorders, focusing on both clinical and animal studies. According to the Substance Abuse and Mental Health Services Administration, cannabis is the most commonly used drug of abuse among adolescents; in 2010, as many as 20% of all 16-year-olds surveyed reported using cannabis. Adolescence refers to the developmental time period between childhood and adulthood and is generally considered to occur from 12 to 17 years of age Spear, . This peCannabinoid type 1 receptors (CB1R), type 2 receptors (CB2R), and their endogenous ligands  anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are present and active during early brain development   and positron emission tomography (PET) studies have reported reduced overall cortical gray matter and increased white matter volume in adolescent cannabis users compared to users who began using cannabis in adulthood  include a “loss of control,” thought disturbances, feelings of unreality, apprehension, fear and paranoia, depersonalization, dysphoria, difficulty concentrating, hallucinations, and other perceptual alterations , two functions that are severely compromised in schizophrenia. Indeed, post-mortem analyses revealed that the density of CB1R receptors was higher in the dorsolateral PFC and cingulate cortices (both anterior and posterior) of schizophrenic patients compared to controls, and these changes were apparently independent of recent pre-mortem cannabis use  lowers AEA levels to normal. Because paranoid schizophrenia is characterized primarily by predominantly positive symptoms due to hyper-dopaminergic neurotransmission  may be associated with an increased risk of developing hebephrenic  schizophrenia  were more vulnerable to the impact of heavy cannabis use, as they showed greater white matter volume decrease and cognitive impairment than patients without heavy cannabis use. These results are suggestive of gene-environment interactions for conferring phenotypic abnormalities in schizophrenia  gene, which encodes an enzyme that degrades catecholamines such as dopamine (DA). The human COMT gene has two allelic variants that code for either a valine or a methionine at codon 158. The functional COMT valine 158 variant catabolizes synaptic DA faster than the COMT methionine 158 variant .Animal models are useful tools for investigating the long-term behavioral effects of cannabis exposure during adolescence. To develop a suitable animal model, one must first take into consideration the obvious differences in developmental ontogeny between the animal species and human patients. Adolescence has a broad developmental border in both humans and animals. In rodents, adolescence ranges from postnatal day 28 (PND28) to PND42 Spear, , and it The relevant literature regarding the long-term consequences of cannabinoid exposure during adolescence in rats is summarized in Table Chronically exposing adolescent rats (of either gender) to CB1R agonists  induces short-term memory impairment measured using the object recognition task  rats with WIN55,212-2 or THC led to decreased sucrose preference (a measure of anhedonia) in adulthood . Impaired PPI is widely accepted as an endophenotype of schizophrenia with high translational validity  with the cannabinoid agonist WIN55,212-2 induced long-lasting sensorimotor gating impairment in adulthood , measured using the PPI test  were exposed to THC during adolescence (the “second hit”); this two-hit approach induced long-lasting impairments in exploration, spatial working memory, and anxiety  gene. Mice that are heterozygous for the transmembrane domain Nrg1 mutant (Nrg1 HET mice) appeared to be more sensitive to the behavioral effects of acute THC exposure than their wild-type littermates  mice developed tolerance to cannabinoid-induced anxiety, whereas Nrg1 HET mice showed a persistent anxiogenic response to chronic cannabinoid exposure. Cannabinoid exposure (either acute or chronic) also selectively induced the expression of Fos transcription factors in the lateral septum of Nrg1 HET mice, but not wild-type mice (Boucher et al., Nrg1 HET mice to THC exacerbated their hyperlocomotor phenotype and induced differential effects in the density of NMDA, CB1, and 5-HT2A receptors in brain regions that are relevant to schizophrenia, particularly the hippocampus (Long et al., Nrg1 gene can modulate the behavioral consequences of THC exposure during adolescence.Other studies have also revealed an interesting interaction between cannabis exposure and a mutation in the Similarly, Schneider and Koch  reportedTaken together, these studies of the interaction between genetic factors and environmental factors help elucidate the putative mechanisms underlying the etiopathogenesis of schizophrenia and may facilitate the discovery of new therapeutic targets.A considerable body of evidence obtained from both human studies and animal models suggests that cannabis use during adolescence increases the risk of developing a psychiatric disorder in adulthood, including anxiety, depression, and schizophrenia. The psychiatric disorders discussed in this review are multifactorial in origin, and the transition from adolescent cannabis use to subsequent psychiatric illness may also involve both genetic factors and environmental factors. The developmental period of initiation, the frequency, and the duration of cannabis use, as well as any underlying psychiatric pathology, may all play a critical role in the development of a psychiatric disorder. In addition, compelling evidence suggests that some adolescents are more susceptible to the long-term effects of cannabis use than others, and this may be due to differences in genetic vulnerability, including polymorphisms in the genes that play a role in the development of psychiatric diseases. However, whether early cannabis use is related to a pre-existing pathology that is exacerbated by drug use remains an open question.Disrupting the eCB system during development may affect several neurotransmitter systems. Indeed, CB1R receptors are presynaptic and are expressed primarily in GABAergic interneurons and pyramidal neurons (Marsicano and Lutz, Longitudinal studies using neuroimaging and genetic approaches to evaluate adolescents prior to the start of chronic cannabis use are needed. In addition, studies using animal models are needed in order to further investigate the role of the endocannabinoid system in adolescence, as well as the molecular and neurochemical mechanisms that underlie the deleterious effects of cannabinoid exposure during adolescence. Such studies would greatly enhance our understanding of the propensity for adolescent cannabis use to facilitate the development of psychiatric disease later in life.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.


Histologically, it is organized into six horizontal layers, each containing unique populations of molecularly and functionally distinct excitatory projection neurons and inhibitory interneurons. The stereotyped cellular distribution of cortical neurons is crucial for the formation of functional neural circuits and it is predominantly established during embryonic development. Cortical neuron development is a multiphasic process characterized by sequential steps of neural progenitor proliferation, cell cycle exit, neuroblast migration and neuronal differentiation. This series of events requires an extensive and dynamic remodeling of the cell cytoskeleton at each step of the process. As major regulators of the cytoskeleton, the family of small Rho GTPases has been shown to play essential functions in cerebral cortex development. Here we review  In humans, the cerebral cortex is responsible for the processes of thought, perception and memory and serves as the seat of advanced motor functions, social abilities and language. These functions relies on the proper development of two main populations of neurons, projection or pyramidal neurons, which are glutamatergic and excitatory, and interneurons, which are GABAergic and inhibitory. Neurons in the cerebral cortex are arranged into six distinct layers different in terms of connectivity, gene expression profile and birthdate . At early developmental stages, around E10 in mouse, NEs along the dorsal surface of lateral ventricles self-renew to expand the progenitor pool and then convert into cells expressing glial markers such as the astrocyte-specific glutamate transporter (GLAST) and brain lipid-binding protein (BLBP), the radial glial cells (RGs). The asymmetric divisions of these RGs are responsible for producing cortical projection neurons either directly or indirectly through intermediate progenitor cells (IPs) or outer radial glial cells (oRGs). Newborn projections neurons then migrate radially in a step-wise fashion to their final destination using RG fibers as a scaffold and finally undergo terminal differentiation to transmit and receive information. As neurogenesis progresses, diverse subtypes of projection neurons are generated sequentially and their migration occurs in an inside-out manner: neurons generated first occupy the deepest layers of the future six layered neocortex whereas later born neurons by-pass earlier born neurons and settle in more superficial layers  and GDP (inactive)—bound states. The GDP/GTP cycle is promoted by the activity of two classes of molecules, guanine nucleotide exchanging factors (GEFs) and GTPase activating proteins (GAPs). GEFs facilitate the exchange of GDP with GTP, resulting in protein activation. GAPs instead stimulate the intrinsic enzymatic activity of the GTPases, which promotes hydrolysis of GTP into GDP. GAP activity therefore ends the cycle and returns the GTPases in their inactive state  where neurons migrate or settle at the end of their migration  in layer V and to a lesser extent in layers II-III  with neighboring RGs Figure , ❶, and RhoA by CreFoxG1 , a process whereby nuclei change position along the apico–basal axis during the course of the cell cycle. In NEs, this INM spans the entire apical–basal axis of the cell, with the nucleus migrating to the basal side during the G1 phase of the cell cycle, staying at the basal side during S phase, migrating back to the apical side during the G2 phase and undergoing mitosis at the ventricular surface. In RGs, the same mitotic behavior occurs, except that is confined to the portion of the cell in the VZ Figure , ❷. As aCdc42 deficient mice , demonstrating that Rnd3-mediated disassembly of actin filaments coordinates the cellular behavior of RGs during INM at least during the apical nuclear movement  during the period of symmetrical division prior to neurogenesis, and throughout the period of asymmetrical division during neurogenesis Figure , ❸ Mori. In thesRnd3 is knockdown the fraction of RGs dividing with an oblique or horizontal cleavage plane is increased , where they acquire a multipolar shape Figure , ❹. DuriRac1 in the forebrain, in utero electroporation of DN or constitutively active (CA) forms of Rac1 as well as Rac1 shRNA or wild-type Rac1 have demonstrated a requirement for this Rho GTPase in radial migration  induces a similar phenotype  or CA-Cdc42 (V12Cdc42) are electroporated in utero, radial migration is inhibited but this effect is not as strong as that seen with DN-Rac1 or CA-Rac1 , and migrate radially leaving the tangential process behind, forming an “L-shaped” axon Figure , ❻ Hata. Thus, din vitro and reviewed elsewhere , Myo9b and RICS, as well as GEFs like kalirin  is specifically expressed in neurons, Sanno and colleagues have demonstrated that the inhibition of RhoA activity reduces the amount of apoptosis occurring in the postnatal cortex and results in a concomitant increase in the density and absolute number of neurons in the adult cortex  are integrated in nascent cortical neurons and how they are spatially and temporally controlled during cortical development.in vivo thus represent an underexplored territory that may hold therapeutic potential.Abnormal signaling through Rho GTPases is associated with cognitive dysfunction (Newey et al., 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.


One in six people worldwide will experience a stroke in his/her lifetime. While people in Africa carry a disproportionately higher burden of poor stroke outcomes, compared to the rest of the world, the exact contribution of genomic factors to this disparity is unknown. Despite noteworthy research into stroke genomics, studies exploring the genetic contribution to stroke among populations of African ancestry in the United States are few. Furthermore, genomics data in populations living in Africa are lacking. The wide genomic variation of African populations offers a unique opportunity to identify genomic variants with causal relationships to stroke across different ethnic groups. The Stroke Investigative Research and Educational Network (SIREN), a component of the Human Health and Heredity in Africa (H3Africa) Consortium, aims to explore genomic and environmental risk factors for stroke in populations of African ancestry in West Africa and the United States. In this article, we review the literature on the genomics of stroke with particular emphasis on populations of African origin. Stroke is the clinical culmination of several complex processes and interacting pathways that involve various genetic and environmental factors.The diverse genomic variation of African populationsIn this review article, we provide an overview of the changing global and in particular, African epidemiology of stroke, the known peculiarities of stroke in Africa, extant literature on the genomics of stroke and cerebrovascular risk factors, with particular attention to people of African ancestry, as well as opportunities for charting new paths through the Human, Health and Heredity in Africa (H3Africa) initiative.12Stroke has attracted global attention, as one in six people will develop stroke in their lifetime.Africa, in epidemiological transition,The burgeoning incidence of stroke in Africa is attributable to rising cardiovascular risk profile, which is in turn driven by epidemiological transition, an aging population, rapid urbanisation and accompanying lifestyle changes. Africa, with a current population of over one billion, has a stroke prevalence rate of up to 963/100 000 population,26Enhanced predisposition, different pattern of subtypes, worse severity and often poorer outcome of stroke in people of African descent is quite well established. According to data from the INTERSTROKE study, ischaemic stroke accounts for 66% while haemorrhagic stroke accounts for 34% in Africa, compared to 91 and 9%, respectively for ischaemic and haemorrhagic stroke in HIC. Ischaemic stroke subtypes diagnosed in African populations were small vessel 27%), cardio-embolism (25%), large vessel (14%), others (20%) and undetermined (14%).%, cardioAmong sub-Saharan Africans, stroke affects a relatively younger age group and productive workforce than in developed economies.33Genetics and genomics research offer insight into disparities in the risk profile, phenotypes and outcome of diseases among different populations as a result of accumulated small differences in common alleles or rare variants, interactions among multiple genetic loci and interactions between genes and environmental factors, which may include cultural practices and health-seeking behaviour.36African populations present the highest genomic diversity, the lowest levels and most divergent patterns of linkage disequilibrium, as well as smaller haplotype block sizes across human populations.8,37 Although the human species is believed to have originated from Africa about 200 000 years ago, studies of genomic variation in Africa suggest that the present pattern of variation within and between populations is a product of several factors. These include demographic history, population structure, diversities of geographical location, language classification and different patterns of subsistence, dietary differences, multiple migrations with accompanying high levels of genetic admixture and survival related to exposure to infectious diseases.38,39For example, Tishkoff and colleaguesMore recently, Shriner and colleaguesOur knowledge of African human genomic variation is growing. This was previously limited by the small number of African populations involved in landmark projects such as the International HapMap projectHowever, recent data from the African Genome Variation project (AGVP) have provided evidence and more detailed characterisation of African genomic diversity.ATP1A1 and AQP2), deregulation of AQP2 expression, and loss-of-function mutations in ATP1A1 have been associated with essential and secondary hypertension, respectively.12These admixtures provide evidence for back-to-Africa migration, the existence of hunter–gatherer populations in West Africa and a pattern of gene flow consistent with the Bantu expansion. The AGVP also found new loci related to susceptibility, pathogenesis, severity and outcome of several diseases, including malaria, Lassa fever, trypanosomiasis, trachoma and hypertension. For instance, they identified highly differentiated variants within genes involved in osmoregulation ,39Genomic variation and related phenotype data on variable traits contribute novel information useful for identifying population-specific variants that play a role in gene function, phenotypic adaptation and susceptibility to complex diseases, such as stroke in Africans and populations of African descent. The APOE ε4 allele, a well-studied example that contributes to a small extent to individual and population risks of traits such as stroke, heart disease and dementia, is found in virtually all populations, albeit at varying rates. The frequency of homo- or heterogeneous APO ε4 alleles varies across populations but confers different attributable risks of Alzheimer’s disease; the risk being higher among the Japanese but much lower among people of African ancestry with higher allele frequencies. This suggests possible intervening roles for epigenetic interactions from certain modifier genes or some other environmental factors.34Stroke is a complex polygenic, heterogeneous and multifactorial disorder involving many complex mechanisms, intermediate phenotypes and the interplay of genetic and non-genetic factors. Evidence from twin studies, family history studies, animal models and heritability studies of vascular risk factors and intermediate phenotypes suggests a likely significant contribution of genetic factors to the neurobiology and phenomenology of stroke.46Among individuals with a positive family history of stroke, there is an increased risk of stroke, which may be due to expression of genetic susceptibility, a shared environment or both.48p = 0.003) while a positive family history was a risk factor for stroke in both case–control  and cohort  studies. Besides, positive family history was more associated with small-vessel and large-vessel strokes.49In a systematic review of the heritability of stroke in 53 independent studies , it was found that monozygotic twins were more likely to be concordant than dizygotic twins  and carotid intima–media thickness (CIMT). For instance, research evidence has shown racial and ethnic disparities in cardiovascular and cerebrovascular diseases, with Americans of African ancestry showing a higher prevalence of hypertension and earlier onset, and faster and more severe end-organ damage, including stroke.32PMS1, SLC24A4, YWHA7, IPO7 and CACANA1H with systolic blood pressure levels, with significant replication of some single-nucleotide polymorphisms (SNPs) in a sample of West Africans.53A recent genome-wide association study (GWAS) of hypertension and blood pressure in African Americans using the pathway-focused approach established the genome-wide significant association of the genetic variants In the GenHAT study evaluating the pharmacogenetic effects of candidate gene complexes on stroke, significant genetic difference was found between hypertension drug treatment groups in patients who had experienced stroke, especially among African Americans and non-Hispanic whites.A Nigerian study assessed glucose and insulin responses to an oral glucose load among offspring of parents with type 2 diabetes mellitus (T2DM) and found higher levels of fasting plasma glucose, fasting plasma insulin, and two-hour post-glucose load plasma insulin, indicating a higher risk for developing diabetes.56The Africa America Diabetes Mellitus (AADM) study has utilised genome-wide linkage and association studies to provide insight into the genomics of T2DM in Niger-Kordofanian African populations of Nigeria and Ghana. Multiple linkage analysis provided evidence of regions of chromosome 12, 19 and 20 (the strongest being 20q13.3).57APOL1) gene has been identified as a risk locus for CKD in African Americans, and replications confirmed in Nigerian Yoruba CKD patients.62Chronic kidney disease (CKD) is an identified risk factor for cerebral vascular disease.APOL1 confers resistance to infection from Trypanosoma brucei brucei, one of the trypanosomes that cause African sleeping sickness and it is believed that its evolutionary history lies in its positive selection due to its protection against sleeping sickness.APOL1 gene.12In Africa, Population-attributable risks of genetic variants differ depending on whether they are monogenic, common variants or rare variants of multiple genes of polygenic disorders.Both twin and family studies have shown that magnetic resonance imaging of white matter hyperintensities has shown a heritability (proportion of variation explained by genetic factors) of up to 70%.67Monogenic disorders may cause stroke as part of multi-systemic manifestations or solely as a clinical phenotype limited to the central nervous system. They are important for individual patients but may not account for much population-attributable risk.46Sickle cell disease (SCD) is of particular importance in people of African ancestry. It is caused by a point mutation at codon 6 of the beta-globin gene, leading to a glutamic acid to valine  substitution in the beta-globin chain of human adult haemoglobin, and producing sickle haemoglobin (HbS). Inherited autosomal recessively, either two copies of HbS or one copy of HbS plus another beta-globin variant (such as HbC) are required for disease expression. HbS carriers are protected from malaria infection, and this selective pressure is believed to have led to the high frequency of HbS (up to 40%) in individuals of African ancestry, especially in areas of high malaria endemicity.69The spread of SCD to the Americas is inextricably linked to slavery and the large-scale forced translocation of populations from West Africa.72ANXA2, rs11853426, TEK rs489347, and TGFBR3 rs284875 variants, have been associated with increased stroke risk.GOLGB1 (Y1212C) and ENPP1 (K173Q) associated with protection from stroke in a cohort of children with sickle cell anaemia.74Certain genetic polymorphisms may be associated with stroke in SCD as modifier genes. For instance whereas α-thalassaemia genes may be protective, mutations in the glucose-6-phosphate dehydrogenase (G6PD) genes and certain SNPs, including However, the interactions between SCD, its associated modifier genes, and environmental factors to produce an intermediate phenotype (TCD velocity > 200 cm/s) and stroke have not been examined in people of indigenous sub-Saharan Africa. Knowledge of these interactions and the metabolic pathways involved may unmask targets for preventative and therapeutic interventions in the sub-population of people living with SCD.NOTCH3 gene and presents with migraine headache, followed by depression and ischaemic stroke in the deep gray structures and subcortical white matter, cognitive decline, and dementia.NOTCH 3 gene.78Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is associated with mutations in the Genetic linkage studies have contributed to our understanding of the heritability of stroke and especially chromosomal regions and sub-regions involved, even though most studies have focused more on the ischaemic phenotype. PDE4D) and 5-lipoxygenase activating protein (ALOX5AP) genes through linkage analysis by the Icelandic Decode group was a significant landmark in the history of stroke genomics.PDE4D was found to be significantly associated with stroke in current smokers in an African American cohort,NOS3 have also been significantly associated with large-artery stroke in African Americans.IL6R polymorphisms and the kappacasein gene CSN3 found on chromosome 4, the latter through exome sequencing.5Identification of the phosphodiesterase 4D .85The genetics of intracerebral haemorrhage (ICH) has also been explored through a range of candidate gene and GWAS approaches. Genes involved in the renin–angiotensin–aldosterone system, coagulation pathway, lipid metabolism, homocysteine metabolism and inflammation are among the most explored.APOE ε4 genes with deep ICH is rather inconsistent.87The association of MTHFR), interleukin-6, tumour necrosis factor-α, angiotensin converting enzyme (ACE), factor VII, factor XIII, platelet activating factor and β-tubulin, although most are described in populations of non-African ancestry.83Deep ICH is also more aetiologically related to hypertensive chronic small-vessel disease and is likely to be more relevant in African populations where hypertension is the dominant stroke risk factor. Other genes with significant polymorphisms related to ICH include the methylenetetrahydrofolatereductase  and the Wellcome Trust, is currently executing 24 different disease-based projects involving 50 000 to 75 000 participants across the African continent.The H3Africa Consortium is revolutionising genomic research in Africa and closing the huge genomics gap between Africa and the developed world. The initiative will reduce health disparities and enhance understanding of health issues for the benefit of Africans and the human race through the discovery of new genes and disease pathways with therapeutic and preventative potentials.The Stroke Investigative Research and Education Network (SIREN) project is one of the H3Africa-funded projects. The SIREN investigators propose to explore genomic factors in stroke in 6 000 native West Africans (3 000 case–control pairs) in comparison with 1 000 African Americans  and 12 000 Americans of European ancestry in the REGARDS study (comparison among three tracks).The SIREN project has three main streams: phenomics (including community engagement), genomics, and bio-informatics et al.To combat these challenges, the SIREN project has been designed in compliance with the recommendations of Dichgans Understanding the interaction between genetic and environmental conditions that predispose to stroke and impede favourable post-stroke outcomes is crucial for the formulation of targeted treatment strategies aimed at the successful prevention of and recovery from stroke. Unravelling the genomic underpinnings of stroke in populations of African ancestry will greatly improve our broad understanding of the molecular pathways of stroke and likely add substantially to ongoing efforts to mitigate the devastating global consequences of stroke.The negative impact of cultural and religious beliefs, issues of autonomy of decision making and voluntary participation, as well as poor understanding of the health impact of genomics are potential challenges to translating genomic advances into real-world clinical applications in Africa. These suggest that caution should be exercised with regard to the expectations from stroke genomics research in Africa, while rigorous detection, evaluation, treatment and control of high blood pressure cannot be overemphasised as a pragmatic strategy to curtail stroke in Africa.


A hallmark of aging is alteration of organismal homeostasis and progressive decline of tissue functions. Alterations of both cell intrinsic functions and regenerative environmental cues contribute to the compromised stem cell activity and reduced regenerative capability occurring in aged muscles. In this perspective, we discuss the new evidence supporting the hypothesis that skeletal muscle stem cells (MuSCs) are intrinsically defective in elderly muscles. In particular, we review three recent papers leading to identify fibroblast growth factor receptor-1, p38 mitogen-activated protein kinase, and p16INK4a as altered signaling in satellite cells from aged mice. These pathways contribute to age-related loss of MuSCs asymmetric polarization, compromised self-renewal capacity, and acquisition of pre-senescent state. The pharmacological manipulation of those networks can open novel strategies to rejuvenate MuSCs and counteract the functional decline of skeletal muscle during aging. Extended lifespan raises the issue of handling age-related disorders, which profoundly affect the quality of life of an increasing number of people. At the physiological level, the most relevant feature of aging is the functional decline of tissue functions , and other cellular types  that participate in the orchestration of regeneration. Muscle niche derived and systemic cues contribute to regulate muscle homeostasis and functionality  operating in geriatric MuSCs in coincidence with their impaired regenerative potential. Indeed, genetic inactivation of p16INK4a locus was sufficient to recover the cells from the senescence-associated cell cycle arrest and restore their self-renewal capacity, leading to the reconstitution of the stem cell pool after muscle damage. The novelty of this study relies on the finding that geriatric stem cells are associated with the progressive accumulation of DNA damage and senescence-associated markers that in turn contribute to the loss of reversible quiescence mediated by p16INK4a. Indeed, in geriatric MuSCs, the p16INK4a locus is constitutively de-repressed due to altered PRC1 complex function.In the same month Sousa-Victor and colleagues came out with a study demonstrating that geriatric MuSCs fail to support muscle regeneration and display defective activation. Serial transplantation experiments supported the conclusion that this defect is a cell intrinsic feature of geriatric MuSCs. They identify the master regulator of senescence p16INK4a, thus reversing geroconversion and allowing MuSCs to support muscle regeneration (Table INK4a (Serrano et al., INK4a in order to devise treatments aimed at reversing MuSC senescence.These studies demonstrate that in addition to the regenerative environment that profoundly affects the niche and stem cell function, there is another level of tissue homeostasis regulation that is intrinsic to adult stem cells. The cell autonomous functionality declines in the elderly due to de-regulated p38 signaling and accumulation of DNA damage and senescence-associated features. This evidence suggests new avenues to reverse the dysfunctional status of MuSCs from aged tissues. For instance, constitutive FGFR1 signaling can restore MuSCs asymmetric division and self-renewal, and pharmacological blockade of p38 signaling can promote MuSCs self-renewal and engraftment by silencing p16on Table  as well 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.


Dopamine (DA) transmission in brain areas such as the prefrontal cortex (PFC) and nucleus accumbens (NAcc) plays important roles in cognitive and affective function. As such, DA deficits have been implicated in a number of psychiatric disorders such as schizophrenia and attention deficit/hyperactivity disorder (ADHD). Accumulating evidence suggests that DA is also involved in social behavior of animals and humans. Although most animals organize and live in social groups, how the DA system functions in such social groups of animals, and its dysfunction causes compromises in the groups has remained less understood. Here we propose that alterations of DA signaling and associated genetic variants and behavioral phenotypes, which have been normally considered as “deficits” in investigation at an individual level, may not necessarily yield disadvantages, but even work advantageously, depending on social contexts in groups. This hypothesis could provide a novel insight into our understanding of the biological mechanisms of psychiatric disorders, and a potential explanation that disadvantageous phenotypes associated with DA deficits in psychiatric disorders have remained in humans through evolution. Dopamine (DA) plays important roles in various aspects of brain function , and substantia nigra pars compacta (SNc) , respectively, are involved in cognitive functions such as working memory  single nucleotide polymorphism (SNP: rs4680) on the gene coding catechol-o-methyl transferase (COMT)  knockout mice  plays significant roles in social function of non-human primates  allele (rs1800497) which is one of the polymorphisms associated with DA D2 receptor function, although its location is not exactly within the DRD2 gene, and the adjunct gene encoding that encodes ankyrin repeat and kinase domain containing 1 (ANKK1) gene. Large social network studies have shown a positive correlation between the DRD2/ANKK1 TaqI A genotypes and friendships in the network, such that individuals with the same genotypes tend to create friendships    has been found in rhesus macaques, with the 7-repeat (7R) allele resulting in lower MAOA activity than the 5- and 6-repeat (5R/6R) alleles  social contexts and unusual  environments provokes some insights. Unfortunately, most previous studies have been conducted at an individual level, and their results are interpreted in “normal” (modern human) social contexts.For instance, that consideration of brain function and dysfunction including those associated with DA signaling in animal socioecological contexts is a promising approach is illustrated by a study investigating the effects of the N-methyl-d-asparate (NMDA) antagonist phencyclidine (PCP) in socially housed capuchin monkeys  housed in the semi-natural social group (unpublished observation). In this study, the effects of chronic dopamine D1 antagonist administration were examined in the second ranked subject within the social group. Before drug administration, the second ranked subject did not have food access before the first ranked subject. However, after drug administration, the second ranked subject had now frequently obtained foods even before the first ranked subject accessed. Nevertheless, the subject receiving drug administration did not have increased aggressive attacks from any other subjects including the first ranked subject in the group at any experimental stages. Since the experiment was conducted in a group of monkeys, it is hard to apply conventional cognitive and sensorimotor tests in the animal to examine the effects of drug administration. However, a persistent decrease in a number of goal directed actions after drug administration was observed, suggesting that cognitive process may be disturbed by drug administration. In addition, this experiment has hitherto been conducted only in a single animal, and therefore, awaits replications in future investigation. Nevertheless, the results suggest that behavioral traits associated with low DA D1 signaling may not be interpreted as “deficits,” but rather “beneficial” in the social contexts of animals such as Japanese macaques.There are very few, if any, studies that have investigated D1 receptor function in animals living in a socially natural environment. We have recently conducted an experiment to investigate the effects of chronic administration of the D1 antagonist in a Japanese macaque  brain developmental periods Figure . ConsequThe other mechanism may involve selection of a genotype under unique  environmental and social conditions Figure . Thus, aA recent epidemiological study has reported that fecundity rates in psychiatric patients are decreased compared to normal subjects (Power et al., de novo mutations of the genes are a significant mechanism that causes psychiatric disorders such as schizophrenia and autism spectrum disorder, and could account for constant prevalence of these disorders (Sullivan et al., de novo mutations could account for only a small percentage of cases, and a majority of cases is still caused by additive effects of multiple common genetic variants with each gene variant contributing a small effect (Mcclellan et al., de novo mutations. Moreover, even if such de novo mutations were the major mechanism that causes psychiatric disorders, it is still unclear why specific neural systems such as the DA system have been chosen to be altered in these psychiatric disorders.Accumulating evidence suggests Indeed, behavioral traits associated with psychiatric disorders are thought to have emerged at some points of evolution, and have been inherited into humans. A number of hypotheses have been proposed, arguing that some aspects of psychiatric symptoms associated with DA alterations operate advantageously in specific environmental contexts. For instance, ADHD is one of such psychiatric disorders in which DA deficits have been implicated, but advantageous aspects of its symptoms are relatively clear. The core symptoms of ADHD consist of hyperactivity, impulsivity, and inattention, all of which involve DA signaling. Administration of DA agonists such as psychostimulants causes hyperlocomotion in rodents (Vanderschuren and Kalivas, Psychiatric disorders in which DA deficits are implicated exhibit cognitive dysfunction. Such cognitive deficits are often similar, if not identical, across different disorders. For instance, impulsivity is a behavioral trait that is observed not only in ADHD, but also in other psychiatric disorders such as schizophrenia Ouzier, , obsessiIn this article, we have presented the concept, along with supporting literatures, that alterations of the DA system associated with psychiatric disorders such as schizophrenia may not necessarily work disadvantageously in specific socioecological contexts of animals such as non-human primates. This may provide biological explanations why genetic variants on several psychiatric disorder-associated genes such as DRD2 and COMT have been selected or maintained through evolution in humans. Reconsideration of psychiatric disorders with DA deficits from an evolutionary perspective would yield novel insights into our understanding, and open a new venue on research unveiling the biological mechanisms, and thereby prevention and therapeutic treatments, of psychiatric disorders.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.


NG2 cells, also referred to as oligodendrocyte precursor cells (OPCs) or polydendrocytes, represent a major resident glial cell population that is distinct from mature astrocytes, oligodendrocytes, microglia, and neural stem cells and exist throughout the gray and white matter of the developing and mature central nervous system (CNS). While their most established fate is the oligodendrocyte, they retain lineage plasticity in an age- and region-specific manner. During development, they contribute to 36% of protoplasmic astrocytes in the ventral forebrain. Despite intense investigation on the neuronal fate of NG2 cells, there is no definitive evidence that they contribute substantially to the neuronal population. NG2 cells have attributes that suggest that they have functions other than to generate oligodendrocytes, but their exact role in the neural network remains unknown. Under pathological states, NG2 cells not only contribute to myelin repair, but they become activated in response to a wide variety of insults and could play a primary role in pathogenesis. NG2 cells represent a resident glial progenitor cell population that exists throughout the gray and white matter of the developing and mature mammalian central nervous system (CNS) and are distinct from astrocytes, mature oligodendrocytes, microglia, and neural stem cells -CreER transgenic mouse lines observed reporter+ neurons in the piriform cortex , transit-amplifying cells (type C cells), and neuroblasts that migrate to the olfactory bulb via the rostral migratory stream (type A cells)  (Lee et al., 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.


It has been recognized for some time that different subtypes of cortical inhibitory interneurons innervate specific dendritic domains of principal cells and release GABA at particular times during behaviorally relevant network oscillations. However, the lack of basic information on how the activity of interneurons can be controlled by GABA released in particular behavioral states has hindered our understanding of the rules that govern the spatio-temporal organization and function of dendritic inhibition. Similar to principal cells, any given interneuron may receive several functionally distinct inhibitory inputs that target its specific subcellular domains. We recently found that local circuitry of the so-called interneuron-specific (IS) interneurons is responsible for dendritic inhibition of different subtypes of hippocampal interneurons with a great impact on cell output. Here, we will review the properties and the specificity of connections of IS interneurons in the CA1 hippocampus and neocortex, and discuss their possible role in the activity-dependent regulation of dendritic inhibition received by pyramidal neurons. In neocortical and hippocampal networks, a large diversity of GABAergic inhibitory inputs converges onto the dendrites of glutamatergic principal cells. Many of them may overlap within the same dendritic domain but remain segregated temporally due to specific inhibitory mechanisms that evolved to control the activity of dendrite-targeting interneurons. The vasoactive intestinal polypeptide (VIP) and/or calretinin (CR) expressing interneurons have been consistently associated with cortical dendritic disinhibition. For example, in the CA1 hippocampal area, three types of the so-called interneuron-specific (IS) interneurons have been shown to make symmetric contacts with interneurons selectively  located in PYR or RAD with 2–3 primary dendrites of unipolar or bipolar orientation extending towards LM or LM and O/A, respectively Figures . In mostP Figure .In acute hippocampal slices, IS3 cells have a resting membrane potential of −64 to −75 mV, suggesting that these cells are likely silent under basal conditions. However, compared with other interneuron subtypes, IS3 interneurons have a particularly high input resistance (400–600 MΩ) and a small rheobase (30–50 pA), which makes them one of the most excitable interneuron subtypes in the hippocampus. The properties of the action potential, including the spike threshold, the amplitude and the half-width are similar to those in other types of neurons , making up ~40% of 5HT3aR+ interneurons . For example, in anesthetized animals, OLM cells were quiet during SWRs (Klausberger et al., in vitro could fire at a later phase of SWRs (Pangalos et al., in vivo and, subsequently, modulate the activity of OLM interneurons.Under what network conditions might this happen Recent experimental observations obtained from different neocortical regions highlight the idea that disinhibitory VIP+ interneurons may be engaged in network activity during specific behavioral states (Lee et al., In conclusion, recent studies from several laboratories provided direct experimental evidence that cortical IS interneurons may play a major role in the state-dependent gating of information flow across cortical regions primarily through dendritic disinhibition of principal neurons. By controlling dendritic electrogenesis and firing mode of principal cells, IS interneurons may determine the functional output of intracortical processing during specific brain states. Future experiments studying the impact of specific connections and their modulation will be required to understand the role of VIP+ interneurons in gating and consolidation of cortical information.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.