Abstract
SIL1 is a nucleotide exchange factor for the molecular chaperone protein Bip in the endoplasmic reticulum that plays a crucial role in protein folding. The Sil1 gene is currently the only known causative gene of Marinesco-Sjögren syndrome (MSS). Intellectual developmental disability is the main symptom of MSS, and its mechanism has not been fully elucidated. Studies have shown that mutations in the Sil1 gene can delay neuronal migration during cortical development, but the underlying molecular mechanisms remain unclear. To further identify potential molecules involved in the regulation of central nervous system development by SIL1, we established a cortical neuron model with SIL1 protein deficiency and used proteomic analysis to screen for differentially expressed proteins after Sil1 silencing, followed by GO functional enrichment and protein‒protein interaction (PPI) network analysis. We identified 68 upregulated and 137 downregulated proteins in total, and among them, 10 upregulated and 3 downregulated proteins were mainly related to actin cytoskeleton dynamics. We further validated the differential changes in actin-related molecules using qRT‒PCR and Western blotting of a Sil1 gene knockout (Sil1-/-) mouse model. The results showed that the protein levels of ACTN1 and VIM decreased, while their mRNA levels increased as a compensatory response to protein deficiency. The mRNA and protein levels of IQGAP1 both showed a secondary increase. In conclusion, we identified ACTN1 and VIM as the key molecules regulated by SIL1 that are involved in neuronal migration during cortical development.