SIL1, a causative cochaperone gene of Marinesco-Söjgren syndrome, plays an essential role in establishing the architecture of the developing cerebral cortex.
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.
Department of Molecular Neurobiology, Institute for Developmental Research, Kasugai Aichi, Japan.
Yutaka
Y
Inaguma
Nanako
N
Hamada
Hidenori
H
Tabata
Ikuko
I
Iwamoto
Makoto
M
Mizuno
Yoshiaki V
YV
Nishimura
Hidenori
H
Ito
Rika
R
Morishita
Motomasa
M
Suzuki
Kinji
K
Ohno
Toshiyuki
T
Kumagai
Koh-ichi
K
Nagata
D000293:Adolescent; D000328:Adult; D000818:Animals; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000254:growth & development* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013132:Spinocerebellar Degenerations / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*
D000091342:Endoplasmic Reticulum Chaperone BiP; D020662:Guanine Nucleotide Exchange Factors; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D034741:RNA, Small Interfering; C418483:SIL1 protein, human