Functional Characterization of Neurofilament Light Splicing and Misbalance in Zebrafish.
Neurofilaments (NFs), a major cytoskeletal component of motor neurons, play a key role in the differentiation, establishment and maintenance of their morphology and mechanical strength. The de novo assembly of these neuronal intermediate filaments requires the presence of the neurofilament light subunit (NEFL), whose expression is reduced in motor neurons in amyotrophic lateral sclerosis (ALS). This study used zebrafish as a model to characterize the NEFL homologue neflb, which encodes two different isoforms via a splicing of the primary transcript (neflbE4 and neflbE3). In vivo imaging showed that neflb is crucial for proper neuronal development, and that disrupting the balance between its two isoforms specifically affects the NF assembly and motor axon growth, with resultant motor deficits. This equilibrium is also disrupted upon the partial depletion of TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein encoded by the gene TARDBP that is mislocalized into cytoplasmic inclusions in ALS. The study supports the interaction of the NEFL expression and splicing with TDP-43 in a common pathway, both biologically and pathogenetically.
['Demy|Doris Lou|DL|', 'Campanari|Maria Letizia|ML|', 'Munoz-Ruiz|Raphael|R|', 'Durham|Heather D|HD|', 'Gentil|Benoit J|BJ|', 'Kabashi|Edor|E|']
D000818:Animals D001284:Atrophy D001369:Axons D002460:Cell Line D004268:DNA-Binding Proteins D004625:Embryo, Nonmammalian D018507:Gene Expression Regulation, Developmental D006801:Humans D009043:Motor Activity D009046:Motor Neurons D016900:Neurofilament Proteins D010641:Phenotype D058105:Polymerization D004856:Postural Balance D012326:RNA Splicing D017386:Sequence Homology, Amino Acid D015027:Zebrafish D029961:Zebrafish Proteins
zebrafish neurofilaments (NFs) amyotrophic lateral sclerosis (ALS), neurofilament light (NEFL), TDP-43