Journal Article

Zebrafish as a Model to Investigate Dynamin 2-Related Diseases

Gaudenzi, Germano, Cotelli, Franco, Blasevich, Flavia, Mora, Marina, Giunta, Michele, Pavesi, Giulio, Bragato, Cinzia, Maggi, Lorenzo

2016

Overview

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 .

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 64/116 / 692/420/2489/1512 / 692/699/375/374 / Alternative Splicing / Animal models / Animals / Animals, Genetically Modified / Charcot-Marie-Tooth disease / Charcot-Marie-Tooth Disease - genetics / Charcot-Marie-Tooth Disease - pathology / Disease Models, Animal / Dynamin / Dynamin II - deficiency / Dynamin II - genetics / Dynamin II - metabolism / Dynamins - genetics / Dynamins - metabolism / Embryos / Gene Knockdown Techniques / Humanities and Social Sciences / Humans / Morphology / Motor task performance / mRNA / multidisciplinary / Muscle Cells - metabolism / Muscle Cells - pathology / Mutation / Myopathies, Structural, Congenital - genetics / Myopathies, Structural, Congenital - pathology / Myopathy / Neuropathy / Science / Sequence Homology, Nucleic Acid / Zebrafish - genetics / Zebrafish - metabolism / Zebrafish Proteins - genetics / Zebrafish Proteins - metabolism