Insights into wild-type dynamin 2 and the consequences of DNM2 mutations from transgenic zebrafish
| العنوان: | Insights into wild-type dynamin 2 and the consequences of DNM2 mutations from transgenic zebrafish |
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| المؤلفون: | Jonathan R. Volpatti, Lindsay D. Smith, Lacramioara Fabian, James J. Dowling, Mo Zhao |
| المصدر: | Human Molecular Genetics. 28:4186-4196 |
| بيانات النشر: | Oxford University Press (OUP), 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Transcriptional Activation, 0301 basic medicine, Heterozygote, GTPase, Biology, Endocytosis, medicine.disease_cause, Animals, Genetically Modified, Dynamin II, 03 medical and health sciences, 0302 clinical medicine, Membrane fission, Charcot-Marie-Tooth Disease, Genetics, medicine, Animals, Humans, Centronuclear myopathy, Muscle, Skeletal, Molecular Biology, Autosomal dominant centronuclear myopathy, Zebrafish, Genetics (clinical), Dynamin, Mutation, Neuromuscular Diseases, General Medicine, medicine.disease, biology.organism_classification, Cell biology, Disease Models, Animal, Phenotype, 030104 developmental biology, 030217 neurology & neurosurgery |
| الوصف: | 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. |
| تدمد: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddz260 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cc865b286822e1ee4e7db78e7d405d71 https://doi.org/10.1093/hmg/ddz260 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....cc865b286822e1ee4e7db78e7d405d71 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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| DOI: | 10.1093/hmg/ddz260 |