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Molecular and Cellular Biology, January 2008, p. 293-301, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.00473-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Altered Quality Control in the Endoplasmic Reticulum Causes Cortical Dysplasia in Knock-In Mice Expressing a Mutant BiP{triangledown}

Naoya Mimura,1,2 Shigeki Yuasa,3 Miho Soma,3 Hisayo Jin,1 Keita Kimura,2 Shigemasa Goto,2 Haruhiko Koseki,4 and Tomohiko Aoe1*

Department of Anesthesiology,1 Department of Medicine and Clinical Oncology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-8670,2 Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502,3 Laboratory for Developmental Genetics, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro, Tsurumi, Yokohama 230-0045, Japan4

Received 20 March 2007/ Returned for modification 21 June 2007/ Accepted 2 October 2007

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.

* Corresponding author. Mailing address: Department of Anesthesiology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-8670, Japan. Phone: 81-43-226-2573. Fax: 81-43-226-2156. E-mail: taoe{at}faculty.chiba-u.jp

{triangledown} Published ahead of print on 22 October 2007.

Molecular and Cellular Biology, January 2008, p. 293-301, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.00473-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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