Abstract
We recently reported the importance of Synoviolin in quality control of proteins through the endoplasmic reticulum (ER)-associated degradation (ERAD) system and its involvement in the pathogenesis of arthropathy through its anti-apoptotic effect. For further understanding of the role of Synoviolin in vivo, we generated in this study synoviolin-deficient (syno(-/-)) mice by genetargeted disruption. Strikingly, all fetuses lacking syno died in utero around embryonic day 13.5, although Hrd1p, a yeast orthologue of Synoviolin, is non-essential for survival. Histologically, hypocellularity and aberrant apoptosis were noted in the syno(-/-) fetal liver. Moreover, definitive erythropoiesis was affected in non-cell autonomous manner in syno(-/-) embryos, causing death in utero. Cultured embryonic fibroblasts derived from syno(-/-) mice were more susceptible to endoplasmic reticulum stress-induced apoptosis than those from syno(+/+) mice, but the susceptibility was rescued by overexpression of synoviolin. Our findings emphasized the indispensable role of the Synoviolin in embryogenesis.
Highlights
Quality control of proteins in the endoplasmic reticulum (ER)1 and transcriptional control of the amount of proteins in
Recent studies have shown that functional disorders of the unfolded protein response (UPR) and/or ER-associated degradation (ERAD) system can augment caspasedependent apoptosis of cells treated with some ER stress-inducible chemical agents [13] that are known to disturb proper protein folding in the ER [14]
F1 mice heterozygous for the mutation were viable, fertile, and showed no apparent phenotypic abnormalities. These heterozygous mice were interbred to generate homozygous mutants, and newborn offspring were genotyped, but no synoϪ/Ϫ mice were identified, indicating that loss of Synoviolin is incompatible with normal embryogenesis (Table I). synoϪ/Ϫ Embryos Die in Utero around E13.5—To identify the stage of embryonic development at which the synoviolin
Summary
Recent studies have shown that functional disorders of the UPR and/or ERAD system can augment caspasedependent apoptosis of cells treated with some ER stress-inducible chemical agents [13] that are known to disturb proper protein folding in the ER [14] These results can explain the molecular pathogenesis of certain human diseases that arise from the ERAD system dysfunction. Essential Role of Synoviolin in Embryogenesis neuronal death of the substantia nigra in patients with autosomal recessive juvenile parkinsonism [18] These findings emphasize the importance of the ERAD system in cell survival in both physiological and pathological conditions and that dysfunction of the ERAD system causes various disorders. Our results clearly indicate that Synoviolin plays an indispensable role in maintenance of life
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