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Published on: November 30, 2015
A Zebrafish Model for a Human Myopathy Associated with Mutation of the Unconventional Myosin MYO18B
Ritika Gurung1, Yosuke Ono2,3, Sarah Baxendale4
1A*STAR Institute of Molecular and Cell Biology, Singapore 138673, Singapore.
Abstract:
Myosin 18B is an unconventional myosin that has been implicated in tumor progression in humans. In addition, loss-of-function mutations of the MYO18B gene have recently been identified in several patients exhibiting symptoms of nemaline myopathy. In mouse, mutation of Myo18B results in early developmental arrest associated with cardiomyopathy, precluding analysis of its effects on skeletal muscle development. The zebrafish, frozen (fro) mutant was identified as one of a group of immotile mutants in the 1996 Tübingen genetic screen. Mutant embryos display a loss of birefringency in their skeletal muscle, indicative of disrupted sarcomeric organization. Using meiotic mapping, we localized the fro locus to the previously unannotated zebrafish myo18b gene, the product of which shares close to 50% identity with its human ortholog. Transcription of myo18b is restricted to fast-twitch myocytes in the zebrafish embryo; consistent with this, fro mutant embryos exhibit defects specifically in their fast-twitch skeletal muscles. We show that sarcomeric assembly is blocked at an early stage in fro mutants, leading to the disorganized accumulation of actin, myosin, and α-actinin and a complete loss of myofibrillar organization in fast-twitch muscles.
Insights
Myosin 18B (MYO18B) is crucial for skeletal muscle development. Zebrafish myo18b mutations disrupt sarcomere assembly, causing severe muscle defects and highlighting its role in myofibril organization.
Area of Science:
- Muscle Development
- Genetics
- Molecular Biology
Background:
- Myosin 18B (MYO18B) is an unconventional myosin linked to human tumor progression.
- MYO18B mutations cause nemaline myopathy and developmental defects in mice.
- Zebrafish 'frozen' mutants exhibit immotility and disrupted skeletal muscle birefringence.
Purpose of the Study:
- To investigate the function of Myosin 18B in skeletal muscle development.
- To identify the genetic basis of the zebrafish 'frozen' mutation.
- To elucidate the role of MYO18B in sarcomere organization and myofibrillogenesis.
Main Methods:
- Meiotic mapping to localize the 'frozen' (fro) locus in zebrafish.
- Gene sequencing to identify the zebrafish myo18b gene.
- Analysis of sarcomeric organization in fro mutant embryos.
Main Results:
- The 'frozen' locus was mapped to the zebrafish myo18b gene, sharing ~50% identity with its human ortholog.
- Zebrafish myo18b is transcribed in fast-twitch myocytes.
- fro mutants display blocked sarcomere assembly, disorganized actin, myosin, and α-actinin accumulation, and loss of myofibrillar organization in fast-twitch muscles.
Conclusions:
- Zebrafish myo18b is essential for proper sarcomere assembly and myofibrillar organization in fast-twitch skeletal muscles.
- The study identifies a conserved role for MYO18B in muscle development across species.
- Zebrafish myo18b mutations provide a model for studying nemaline myopathy and muscle development defects.
