SIL1 , a causative cochaperone gene of M arinesco‐ S jögren syndrome, plays an essential role in establishing the architecture of the developing cerebral cortex

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.Subject Categories Genetics; Gene Therapy & Genetic Disease;

BiP and Its Nucleotide Exchange Factors Grp170 and Sil1: Mechanisms of Action and Biological Functions

“…However, as most of these studies were done before mutations in SIL1 were linked to MSS, it is not clear if all of the affected individuals examined had SIL1 mutations. To test the potential role of Sil1 in the cerebral cortex, mouse embryos were electroporated in utero with vectors encoding shRNA targeting SIL1 169 . Defects in neuronal migration were observed at birth in these mice, which were rescued by co-expression of human wild-type Sil1 but not by three MSS-assciated Sil1 mutants.…”

Role of an adaptor protein Lin‐7B in brain development: possible involvement in autism spectrum disorders

“…; Inaguma et al . ). Like these mice, Lin‐7A/B‐double knockout mice did not show morphological alteration in cerebral cortex at the adult stage (Misawa et al .…”

“…Acute knockdown by in utero electroporation can circumvent the compensatory effects of general gene-knockout approaches; indeed, knockout mice for Doublecortin (a causative gene for subcortical band heterotopia encoding a scaffold protein), Sept4 (encoding a cytoskeleton-related molecule related to Parkinson's disease etiology), and Sil1 (a causative gene for Marinesco-Sjogren syndrome encoding a co-chaperone)-deficient mice exhibit no obvious morphological alteration in the cerebral cortex (Corbo et al 2002;Zhao et al 2005;Ihara et al 2007) while acute knockdown of these genes results in defective neuronal migration (Bai et al 2003;Shinoda et al 2010;Inaguma et al 2014). Like these mice, Lin-7A/B-double knockout mice did not show morphological alteration in cerebral cortex at the adult stage (Misawa et al 2001).…”

“…For migration analyses, the distribution of GFPpositive cells in brain slices was quantified as follows. Coronal sections of cerebral cortices containing the labeled cells were classified into four regions, layer II-IV, V-VI, intermediate zone (IZ), and the subventricular zone (SVZ)/ventricular zone (VZ), as described previously (Inaguma et al 2014). After selecting three electroporated brains, the number of labeled cells in each region of one selected slice per each brain was calculated using ImageJ software (an open source image processing program).…”

Contralateral targeting of the corpus callosum

“…Knockdown of Sil1 causes a range of deficits including neuronal migration delay, morphological disorganisation and delayed callosal axon growth into the contralateral hemisphere, as measured by in utero electroporation of L2/3 S1 (Inaguma et al, 2014). Similar defects were found upon disruption of RNA binding protein, fox-1 homolog (C. elegans) 1 (Rbfox1) signalling, which regulates alternative slicing of an array of transcripts .…”