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Zebrafish as a Model to Investigate Dynamin 2-Related Diseases
Cinzia Bragato1, Germano Gaudenzi2, Flavia Blasevich1
1Neuromuscular Diseases and Neuroimmunology Unit, IRCCS Neurological Institute C. Besta, Milano, Italy.
Abstract:
Mutations in the dynamin-2 gene (DNM2) cause autosomal dominant centronuclear myopathy (CNM) and dominant intermediate Charcot-Marie-Tooth (CMT) neuropathy type B (CMTDIB). As the relation between these DNM2-related diseases is poorly understood, we used zebrafish to investigate the effects of two different DNM2 mutations. First we identified a new alternatively spliced zebrafish dynamin-2a mRNA (dnm2a-v2) with greater similarity to human DNM2 than the deposited sequence. Then we knocked-down the zebrafish dnm2a, producing defects in muscle morphology. Finally, we expressed two mutated DNM2 mRNA by injecting zebrafish embryos with human mRNAs carrying the R522H mutation, causing CNM, or the G537C mutation, causing CMT. Defects arose especially in secondary motor neuron formation, with incorrect branching in embryos injected with CNM-mutated mRNA, and total absence of branching in those injected with CMT-mutated mRNA. Muscle morphology in embryos injected with CMT-mutated mRNA appeared less regularly organized than in those injected with CNM-mutated mRNA. Our results showing, a continuum between CNM and CMTDIB phenotypes in zebrafish, similarly to the human conditions, confirm this animal model to be a powerful tool to investigate mutations of DNM2 in vivo.
Insights
Dynamin-2 gene (DNM2) mutations cause centronuclear myopathy (CNM) and Charcot-Marie-Tooth neuropathy (CMT). Zebrafish models reveal a spectrum of defects, linking these DNM2-related diseases and offering insights into in vivo mutation effects.
Area of Science:
- Genetics and Molecular Biology
- Neuroscience
- Developmental Biology
Background:
- Mutations in the dynamin-2 gene (DNM2) are linked to centronuclear myopathy (CNM) and dominant intermediate Charcot-Marie-Tooth neuropathy type B (CMTDIB).
- The precise relationship and phenotypic continuum between these DNM2-related disorders remain incompletely understood.
- Zebrafish offer a valuable in vivo model for studying the functional consequences of human gene mutations.
Purpose of the Study:
- To investigate the in vivo effects of two distinct DNM2 mutations associated with CNM and CMTDIB using a zebrafish model.
- To characterize the phenotypic spectrum arising from specific DNM2 mutations in a developing organism.
- To identify and validate a novel zebrafish dynamin-2a mRNA splice variant with higher homology to human DNM2.
Main Methods:
- Identification of a new zebrafish dynamin-2a mRNA splice variant (dnm2a-v2) with increased similarity to human DNM2.
- Knockdown of zebrafish dnm2a to assess its role in muscle morphology.
- Injection of zebrafish embryos with human mRNAs encoding wild-type or mutated DNM2 (R522H for CNM, G537C for CMT) to study mutation-specific effects.
Main Results:
- Knockdown of zebrafish dnm2a resulted in observable defects in muscle morphology.
- Expression of CNM-associated DNM2 mutation (R522H) led to abnormal secondary motor neuron formation and branching.
- Expression of CMT-associated DNM2 mutation (G537C) caused a complete absence of motor neuron branching and more disorganized muscle morphology compared to CNM mutation.
- A phenotypic continuum between CNM and CMTDIB was observed in zebrafish, mirroring human conditions.
Conclusions:
- The zebrafish model effectively recapitulates key aspects of DNM2-related myopathies, including CNM and CMTDIB.
- Specific DNM2 mutations exhibit distinct effects on motor neuron development and muscle organization.
- This study validates zebrafish as a powerful tool for in vivo investigation of DNM2 mutations and their associated neuropathies.
