Mutation of sec63 in zebrafish causes defects in myelinated axons and liver pathology
| Autor: | Clara Franzini-Armstrong, Ian S. Hakkinen, Matthew G. Voas, William S. Talbot, Kelly R. Monk |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Nervous system
Medicine (miscellaneous) lcsh:Medicine Myelin 0302 clinical medicine Immunology and Microbiology (miscellaneous) Zebrafish Myelin Sheath Genetics 0303 health sciences biology Cysts Liver Diseases RNA-Binding Proteins Endoplasmic Reticulum Stress 3. Good health Cell biology medicine.anatomical_structure Liver lcsh:RB1-214 Research Article Molecular Sequence Data Neuroscience (miscellaneous) General Biochemistry Genetics and Molecular Biology 03 medical and health sciences SEC63 Microscopy Electron Transmission medicine lcsh:Pathology Animals Humans Amino Acid Sequence 030304 developmental biology Base Sequence Sequence Homology Amino Acid Sodium channel Endoplasmic reticulum lcsh:R Membrane Proteins DNA Zebrafish Proteins biology.organism_classification Axons Disease Models Animal Membrane protein nervous system Mutation Unfolded protein response Unfolded Protein Response 030217 neurology & neurosurgery Molecular Chaperones |
| Zdroj: | Disease Models & Mechanisms Disease Models & Mechanisms, Vol 6, Iss 1, Pp 135-145 (2013) |
| ISSN: | 1754-8411 1754-8403 |
| Popis: | Summary Mutations in SEC63 cause polycystic liver disease in humans. Sec63 is a member of the endoplasmic reticulum (ER) translocon machinery, although it is unclear how mutations in SEC63 lead to liver cyst formation in humans. Here, we report the identification and characterization of a zebrafish sec63 mutant, which was discovered in a screen for mutations that affect the development of myelinated axons. Accordingly, we show that disruption of sec63 in zebrafish leads to abnormalities in myelinating glia in both the central and peripheral nervous systems. In the vertebrate nervous system, segments of myelin are separated by the nodes of Ranvier, which are unmyelinated regions of axonal membrane containing a high density of voltage-gated sodium channels. We show that sec63 mutants have morphologically abnormal and reduced numbers of clusters of voltage-gated sodium channels in the spinal cord and along peripheral nerves. Additionally, we observe reduced myelination in both the central and peripheral nervous systems, as well as swollen ER in myelinating glia. Markers of ER stress are upregulated in sec63 mutants. Finally, we show that sec63 mutants develop liver pathology. As in glia, the primary defect, detectable at 5 dpf, is fragmentation and swelling of the ER, indicative of accumulation of proteins in the lumen. At 8 dpf, ER swelling is severe, other pathological features include disrupted bile canaliculi, altered cytoplasmic matrix, and accumulation of large lysosomes. Together, our analyses of sec63 mutant zebrafish highlight the possible role of ER stress in polycystic liver disease and suggest that these mutants will serve as a model for understanding the pathophysiology of this disease and other abnormalities involving ER stress. |
| Databáze: | OpenAIRE |
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