ZFIN ID: ZDB-PUB-191108-20
Insights into wild type dynamin 2 and the consequences of DNM2 mutations from transgenic zebrafish
Zhao, M., Smith, L., Volpatti, J., Fabian, L., Dowling, J.J.
Date: 2019
Source: Human molecular genetics   28(24): 4186-4196 (Journal)
Registered Authors: Dowling, Jim, Zhao, Mo
Keywords: none
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Charcot-Marie-Tooth Disease/genetics
  • Charcot-Marie-Tooth Disease/metabolism
  • Disease Models, Animal
  • Dynamin II/genetics*
  • Dynamin II/metabolism*
  • Endocytosis
  • Heterozygote
  • Humans
  • Muscle, Skeletal/metabolism
  • Mutation*
  • Neuromuscular Diseases/genetics
  • Neuromuscular Diseases/metabolism
  • Phenotype
  • Transcriptional Activation
  • Zebrafish/genetics
  • Zebrafish/metabolism
PubMed: 31691805 Full text @ Hum. Mol. Genet.
Dynamin 2 (DNM2) encodes a ubiquitously expressed large GTPase with membrane fission capabilities that participates in the endocytosis of clathrin-coated vesicles. Heterozygous mutations in DNM2 are associated with two distinct neuromuscular disorders, Charcot-Marie-Tooth Disease (CMT) and autosomal dominant centronuclear myopathy (CNM). Despite extensive investigations in cell culture, the role of dynamin 2 in normal muscle development is poorly understood and the consequences of DNM2 mutations at the molecular level in vivo are not known. To address these gaps in knowledge, we developed transgenic zebrafish expressing either wild type dynamin 2 or dynamin 2 with either a CNM or CMT mutation. Taking advantage of the live imaging capabilities of the zebrafish embryo, we establish the localization of wild type and mutant dynamin 2 in vivo, showing for the first time distinctive dynamin 2 subcellular compartments. Additionally, we demonstrate that CNM-related DNM2 mutations are associated with protein mislocalization and aggregation. Lastly, we define core phenotypes associated with our transgenic mutant fish, including impaired motor function and altered muscle ultrastructure, making them the ideal platform for drug screening. Overall, using the power of the zebrafish, we establish novel insights into dynamin 2 localization and dynamics, and provide the necessary groundwork for future studies examining dynamin 2 pathomechanisms and therapy development.