title: Altered quality control in the endoplasmic reticulum causes cortical dysplasia in knock-in mice expressing a mutant BiP.
abstract: Binding immunoglobulin protein (BiP) 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.
authors.affiliation: Department of Anesthesiology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-8670, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Mimura
authors.forename: Shigeki
authors.initials: S
authors.lastname: Yuasa
authors.forename: Miho
authors.initials: M
authors.lastname: Soma
authors.forename: Hisayo
authors.initials: H
authors.lastname: Jin
authors.forename: Keita
authors.initials: K
authors.lastname: Kimura
authors.forename: Shigemasa
authors.initials: S
authors.lastname: Goto
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Aoe
mesh_terms: D000818:Animals; D001927:Brain Diseases / Q000151:congenital / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000473:pathology; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D012333:RNA, Messenger / Q000235:genetics; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D000091342:Endoplasmic Reticulum Chaperone BiP; D016326:Extracellular Matrix Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000091042:Reelin Protein; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases