Gne depletion during zebrafish development impairs skeletal muscle structure and function

Alon Daya, Gad David Vatine, Michal Becker-Cohen, Tzukit Tal-Goldberg, Adam Friedmann, Yoav Gothilf, Shao Jun Du, Stella Mitrani-Rosenbaum

Research output: Contribution to journalArticlepeer-review

Abstract

GNE Myopathy is a rare recessively inherited neuromuscular disorder caused by mutations in the GNE gene, which codes for the key enzyme in the metabolic pathway of sialic acid synthesis. The process by which GNE mutations lead tomyopathy is not well understood.Byin situ hybridizationandgnepromoter-driven fluorescent transgenic fish generation, we have characterized the spatiotemporal expression pattern of the zebrafish gne gene and have shown that it is highly conserved compared with the human ortholog. We also show the deposition of maternal gne mRNA and maternal GNE protein at the earliest embryonic stage, emphasizing the critical role of gne in embryonic development. Injection of morpholino (MO)-modified antisense oligonucleotides specifically designed to knockdown gne, into one-cell embryos lead to a variety of phenotypic severity. Characterization of the gne knockdown morphants showed a significantly reduced locomotor activity as well asdistortedmuscle integrity, including a reductionin thenumberofmusclemyofibers, even in mild or intermediate phenotype morphants. These findings were further confirmed by electron microscopy studies, where large gaps between sarcolemmas were visualized, although normal sarcomeric structures were maintained. These results demonstrate a critical novel role for gne in embryonic development and particularly in myofiber development, muscle integrity and activity.

Original languageEnglish
Article numberddu045
Pages (from-to)3350-3361
Number of pages12
JournalHuman Molecular Genetics
Volume23
Issue number13
DOIs
StatePublished - Jul 2014

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