Abstract
SUMMARYMutations 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 observed 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.
Highlights
In eukaryotic cells, most proteins destined for membrane insertion or secretion are first processed in the endoplasmic reticulum (ER)
Liver development was abnormal in the sec63st67 mutants; cysts were not observed in the liver or kidneys
Swelling and fragmentation of the ER was observed in cells of the peripheral nervous system (PNS), central nervous system (CNS) and liver, and multiple molecular markers of ER stress were activated in sec63st67 mutants
Summary
Most proteins destined for membrane insertion or secretion are first processed in the endoplasmic reticulum (ER). Nascent polypeptide chains, synthesized by cytoplasmic ribosomes, enter the ER lumen at specialized sites in the ER membrane called translocons, which are complexes of several ER membrane proteins that associate to form a pore (Schnell and Herbert, 2003). Sec , Sec and Sec form the pore, and this trimeric complex is associated with other proteins including ERj1, Sec and Sec in mammals (Meyer et al, 2000; Zimmermann et al, 2006). Mutations in SEC63 cause polycystic liver disease (PCLD) in humans, a progressive disorder characterized by the presence of many (>20) cysts throughout the liver (Davila et al, 2004; Everson et al, 2004). PCLD often co-occurs in patients with autosomal dominant polycystic kidney disease (PCKD), but can exist as a separate disease without kidney cysts (Torres et al, 2007). Polycystic livers can grow up to ten times their normal size, resulting in significant
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