IFITM2 Modulates Endocytosis Maintaining Neural Stem Cells in Developing Neocortex

Abstract Brain development is orchestrated by a complex interplay of genetic and environmental signals, with endocytosis serving as a pivotal process in integrating extracellular cues. However, the specific role of endocytosis in neurogenesis remains unclear. We uncover a critical function of the interferon‐induced transmembrane protein, IFITM2, essential for endocytic processes in radial glial cells (RGCs). IFITM2 is highly expressed near the ventricular surface in the developing brain. Loss of IFITM2 impairs endosome formation and disrupts RGC maintenance. Mechanistically, we confirmed that the YXXø endocytic motif on IFITM2 is essential for its subcellular localization, with mutations in this motif reducing endocytic vesicles. Additionally, the K82 and K87 residues of IFITM2 interact with phosphoinositides to promote endocytic vesicle formation. Polarized localization of phosphatidylinositol 3,4‐bisphosphate (PI(3,4)P2) on the ventricular side suggests its role in vesicle formation. IFITM2 deficiency also leads to reduced phosphorylation of AKT and GSK3β. These findings highlight the essential role of IFITM2 in regulating endocytosis in RGCs, which is critical for maintaining neural stem cells and proper brain development, offering new insights into the connection between cellular signaling and neurogenesis in both mouse and human models.