SIL1, a causative cochaperone gene of Marinesco‐Sjögren syndrome, plays an essential role in establishing the architecture of the developing cerebral cortex

EMBO Molecular Medicine

Yutaka Inaguma²  Nanako Hamada²  Hidenori Tabata²  Ikuko Iwamoto²  Makoto Mizuno²  Yoshiaki V Nishimura²  Hidenori Ito²  Rika Morishita²  Motomasa Suzuki³  Kinji Ohno¹  Toshiyuki Kumagai³ 

[1] Division of Neurogenetics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan;Department of Molecular Neurobiology, Institute for Developmental Research, Kasugai, Aichi, Japan;Central Hospital, Aichi Human Service Center, Kasugai, Aichi, Japan

关键词: axon growth;    corticogenesis;    Marinesco‐Sjögren syndrome;    neuronal migration;    SIL1;   

DOI  :  10.1002/emmm.201303069

来源: Wiley

【 摘 要 】

Abstract

Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessively inherited disorder with mental retardation (MR). Recently, mutations in the SIL1 gene, encoding a co-chaperone which regulates the chaperone HSPA5, were identified as a major cause of MSS. We here examined the pathophysiological significance of SIL1 mutations in abnormal corticogenesis of MSS. SIL1-silencing caused neuronal migration delay during corticogenesis ex vivo. While RNAi-resistant SIL1 rescued the defects, three MSS-causing SIL1 mutants tested did not. These mutants had lower affinities to HSPA5 in vitro, and SIL1-HSPA5 interaction as well as HSPA5 function was found to be crucial for neuronal migration ex vivo. Furthermore time-lapse imaging revealed morphological disorganization associated with abnormal migration of SIL1-deficient neurons. These results suggest that the mutations prevent SIL1 from interacting with and regulating HSPA5, leading to abnormal neuronal morphology and migration. Consistent with this, when SIL1 was silenced in cortical neurons in one hemisphere, axonal growth in the contralateral hemisphere was delayed. Taken together, abnormal neuronal migration and interhemispheric axon development may contribute to MR in MSS.

Synopsis

SIL1 mutations cause Marinesco-Sjögren syndrome. SIL1 is shown to be involved in neuronal morphology and migration and axon network formation. SIL1 mutations may thus contribute to abnormal corticogenesis during development leading to mental retardation

• A new SIL1 gene mutation was found to cause Marinesco-Sjögren syndrome.
• SIL1 is crucial for proper neuronal morphology, migration and axon growth.
• SIL1 may be essential for brain development.
• Defects in the SIL1-HSPA5 chaperone system may cause functional deficiency in brain leading to mental retardation.

【 授权许可】

CC BY   
© 2014 The Authors.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.