小胶质细胞在早期胚胎阶段迁移到大脑皮层。然而,小胶质细胞迁移的确切机制尚不完全清楚.作为一种细胞外基质蛋白,Netrin-1参与调节多种细胞的运动性。在本文中,我们发现Netrin-1在体外促进小胶质细胞BV2的迁移。机制研究表明,GSK3β活性的激活有助于Netrin-1介导的小胶质细胞迁移。此外,整合素α6/β1可能是相关受体。单细胞数据分析显示,与经典受体相比,小胶质细胞中整合素α6亚基和β1亚基的表达更高,包括Dcc,Neo1,Unc5a,Unc5b,Unc5c,Unc5d,和骗局。微尺度热电泳(MST)测量证实整合素α6/β1和Netrin-1之间的高结合亲和力。重要的是,IKVAV肽对整合素α6/β1的激活反映了Netrin-1诱导的小胶质细胞迁移和GSK3激活。最后,radial胶质细胞及其后代中Netrin-1的条件性敲除(CKO)导致早期发育阶段大脑皮层中小胶质细胞数量减少。一起,我们的发现强调了Netrin-1在小胶质细胞迁移中的作用,并强调了其在小胶质细胞相关脑疾病中的治疗潜力.
Microglia migrate to the cerebral cortex during early embryonic stages. However, the precise mechanisms underlying microglia migration remain incompletely understood. As an extracellular matrix protein, Netrin-1 is involved in modulating the motility of diverse cells. In this paper, we found that Netrin-1 promoted microglial BV2 cell migration in vitro. Mechanism studies indicated that the activation of GSK3β activity contributed to Netrin-1-mediated microglia migration. Furthermore, Integrin α6/β1 might be the relevant receptor. Single-cell data analysis revealed the higher expression of Integrin α6 subunit and β1 subunit in microglia in comparison with classical receptors, including Dcc, Neo1, Unc5a, Unc5b, Unc5c, Unc5d, and Dscam. Microscale thermophoresis (MST) measurement confirmed the high binding affinity between Integrin α6/β1 and Netrin-1. Importantly, activation of Integrin α6/β1 with IKVAV peptides mirrored the microglia migration and GSK3 activation induced by Netrin-1. Finally, conditional knockout (CKO) of Netrin-1 in radial glial cells and their progeny led to a reduction in microglia population in the cerebral cortex at early developmental stages. Together, our findings highlight the role of Netrin-1 in microglia migration and underscore its therapeutic potential in microglia-related brain diseases.