Lv Yuqing, Zou Wenzheng, Li Lin, Zhang Shukui, Liang Jiaqi, Pu Jiali, Jiao Jianwei
Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of Science, Beijing, 100101, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Adv Sci (Weinh). 2025 May;12(17):e2501593. doi: 10.1002/advs.202501593. Epub 2025 Mar 7.
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.
大脑发育由遗传和环境信号的复杂相互作用精心编排，内吞作用是整合细胞外信号的关键过程。然而，内吞作用在神经发生中的具体作用仍不清楚。我们发现了干扰素诱导跨膜蛋白IFITM2的关键功能，它对放射状胶质细胞（RGCs）的内吞过程至关重要。IFITM2在发育中的大脑脑室表面附近高度表达。IFITM2的缺失会损害内体形成并破坏RGC的维持。从机制上讲，我们证实IFITM2上的YXXø内吞基序对其亚细胞定位至关重要，该基序中的突变会减少内吞小泡。此外，IFITM2的K82和K87残基与磷酸肌醇相互作用以促进内吞小泡的形成。磷脂酰肌醇3,4-二磷酸（PI(3,4)P2）在脑室侧的极化定位表明其在小泡形成中的作用。IFITM2缺陷还导致AKT和GSK3β的磷酸化减少。这些发现突出了IFITM2在调节RGCs内吞作用中的重要作用，这对维持神经干细胞和正常大脑发育至关重要，为小鼠和人类模型中细胞信号传导与神经发生之间的联系提供了新的见解。
