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神经导向因子 1 是小胶质细胞迁移的重要介质。

Netrin-1 Is an Important Mediator in Microglia Migration.

机构信息

Key Laboratory of Molecular Epigenetics, Ministry of Education and Institute of Cytology and Genetics, Northeast Normal University, Changchun 130024, China.

出版信息

Int J Mol Sci. 2024 Jun 27;25(13):7079. doi: 10.3390/ijms25137079.

DOI:10.3390/ijms25137079
PMID:39000184
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11241722/
Abstract

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.

摘要

小胶质细胞在胚胎早期迁移到大脑皮层。然而，小胶质细胞迁移的确切机制仍不完全清楚。作为细胞外基质蛋白，Netrin-1 参与调节多种细胞的运动。在本文中，我们发现 Netrin-1 促进了体外 BV2 小胶质细胞的迁移。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（包括 Dcc、Neo1、Unc5a、Unc5b、Unc5c、Unc5d 和 Dscam）相比，整合素 α6 亚基和 β1 亚基在小胶质细胞中的表达水平更高。微量热泳动（MST）测量证实了整合素 α6/β1 与 Netrin-1 之间的高结合亲和力。重要的是，用 IKVAV 肽激活整合素 α6/β1 可以模拟 Netrin-1 诱导的小胶质细胞迁移和 GSK3 激活。最后，在早期发育阶段，胶质细胞和其祖细胞中 Netrin-1 的条件敲除（CKO）导致大脑皮层中小胶质细胞数量减少。总之，我们的研究结果强调了 Netrin-1 在小胶质细胞迁移中的作用，并突出了其在与小胶质细胞相关的脑疾病中的治疗潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd3c/11241722/4583b9df9932/ijms-25-07079-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd3c/11241722/b79826bf3bc5/ijms-25-07079-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd3c/11241722/4583b9df9932/ijms-25-07079-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd3c/11241722/73e9ceb9ab2f/ijms-25-07079-g002.jpg
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Microglia colonize the developing brain by clonal expansion of highly proliferative progenitors, following allometric scaling.小胶质细胞通过高度增殖祖细胞的克隆扩增，遵循异速生长比例，在发育中的大脑中定殖。
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