Rer1-mediated quality control system is required for neural stem cell maintenance during cerebral cortex development

Rer1 is a retrieval receptor for endoplasmic reticulum (ER) retention of various ER membrane proteins and unassembled or immature components of membrane protein complexes. However, its physiological functions during mammalian development remain unclear. This study aimed to investigate the role of Rer1 -mediated quality control system in mammalian development. We show that Rer1 is required for the sufficient cell surface expression and activity of gamma-secretase complex, which modulates Notch signaling during mouse cerebral cortex development. When Rer1 was depleted in the mouse cerebral cortex, the number of neural stem cells decreased significantly, and malformation of the cerebral cortex was observed. Rer1 loss reduced gamma-secretase activity and downregulated Notch signaling in the developing cerebral cortex. In Rer1-deficient cells, a subpopulation of gamma-secretase complexes and components was transported to and degraded in lysosomes, thereby significantly reducing the amount of gamma-secretase complex on the cell surface. These results suggest that Rer1 maintains Notch signaling by maintaining sufficient expression of the gamma-secretase complex on the cell surface and regulating neural stem cell maintenance during cerebral cortex development.