SIL1 modulates Reelin signaling during cortical neuron migration

Abstract

Abstract SIL1 , a nucleotide exchange factor for the endoplasmic reticulum chaperone BiP, primarily binds nascent polypeptides to facilitate proper protein folding. It is a causative gene of Marinesco-Sjögren syndrome (MSS). Previous studies have indicated that SIL1 dysfunction disrupts the migration and positioning of cortical neurons during development, thereby impairing the structural establishment of the early neocortex. However, the precise mechanism by which SIL1 deficiency leads to neuronal migration defects remains unclear. Given the critical role of the Reelin signaling pathway in neuronal positioning and cortical lamination, this study focused on elucidating its mechanistic involvement in neuronal migration defects induced by SIL1 deficiency. In this study, we analyzed single-cell sequencing databases to investigate the expression pattern of the SIL1 gene across different stages of human cortical development. The results revealed a progressive increase in SIL1 expression during early corticogenesis, suggesting a potential role of SIL1 in brain development. Further investigation demonstrated that Sil1 knockout significantly delayed cortical neuronal migration and resulted in aberrant neocortical lamination in mice. Using the Sil1 knockout mouse model, we further demonstrated that loss of SIL1 leads to a downregulation of key reelin pathway components, including Reelin, ApoER2, VLDLR, and Dab1, without significantly affecting the expression of integrin signaling proteins. Furthermore, transfection of Sil1 –/– primary cortical neurons with plasmids expressing SIL1, ApoER2, or VLDLR proteins rescued the neuronal migration deficit. Collectively, these data support that SIL1 modulates cortical neuronal migration at least partially through tuning the abundance of core Reelin signaling components including ApoER2, VLDLR and downstream Dab1 cascade.