Altered quality control in the endoplasmic reticulum causes cortical dysplasia in knock-in mice expressing a mutant BiP
Altered quality control in the endoplasmic reticulum causes cortical dysplasia in knock-in mice expressing a mutant BiP
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DOI：
10.1128/mcb.00473-07
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发表时间：
2008-01-01
影响因子：
5.3
通讯作者：
Aoe, Tomohiko
中科院分区：
文献类型：
--
作者：
Mimura, Naoya;Yuasa, Shigeki;Aoe, Tomohiko
结合免疫球蛋白 (RIP) 是一种内质网 (ER) 分子伴侣，对于 ER 功能至关重要。我们检查了表达突变 BiP 的敲入小鼠，以阐明发育和成年期间对 BiP 功能敏感的生理过程。突变体 BiP 缺乏正常情况下将 BiP 从分泌途径返回到 ER 的恢复序列。这使我们能够在不完全消除 BiP 功能的情况下检查 ER 功能缺陷的影响。 BiP纯合突变体新生儿出生后因呼吸衰竭而死亡。除此之外，突变的 BiP 小鼠在大脑皮层和小脑中表现出紊乱的层形成，这是一种 reeler 突变样畸形的神经表型。与表型一致，Cajal-Retzius（CR）细胞不分泌reelin，并且转录后reelin的表达显着降低。此外，还观察到整个大脑尺寸的减小以及 CR 细胞在整个皮质中的明显分散，这与 reeler 表型不同。这些发现表明CR细胞中reelin的成熟和分泌以及其他与神经迁移相关的因素可能对异常的ER质量控制敏感，这可能导致各种神经系统疾病。
Binding immunoglobulin protein (RIP) is an endoplasmic reticulum (ER) molecular chaperone that is central to ER function. We examined knock-in mice expressing a mutant BiP in order to elucidate physiological processes that are sensitive to BiP functions during development and adulthood. The mutant BiP lacked the retrieval sequence that normally functions to return BiP to the ER from the secretory pathway. This allowed us to examine the effects of a defect in ER function without completely eliminating BiP function. The homozygous mutant BiP neonates died after birth due to respiratory failure. Besides that, the mutant BiP mice displayed disordered layer formation in the cerebral cortex and cerebellum, a neurological phenotype of reeler mutant-like malformation. Consistent with the phenotype, Cajal-Retzius (CR) cells did not secrete reelin, and the expression of reelin was markedly reduced posttranscriptionally. Furthermore, the reduction in the size of the whole brain and the apparent scattering of CR cells throughout the cortex, which were distinct from the reeler phenotype, were also seen. These findings suggest that the maturation and secretion of reelin in CR cells and other factors related to neural migration may be sensitive to aberrant ER quality control, which may cause various neurological disorders.