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Gab1 介导 PDGF 信号通路，对少突胶质细胞分化和中枢神经系统髓鞘形成至关重要。

Gab1 mediates PDGF signaling and is essential to oligodendrocyte differentiation and CNS myelination.

机构信息

Department of Physiology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Department of Neurology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

出版信息

Elife. 2020 Jan 16;9:e52056. doi: 10.7554/eLife.52056.

DOI:10.7554/eLife.52056
PMID:31944179
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6984811/
Abstract

Oligodendrocytes (OLs) myelinate axons and provide electrical insulation and trophic support for neurons in the central nervous system (CNS). Platelet-derived growth factor (PDGF) is critical for steady-state number and differentiation of oligodendrocyte precursor cells (OPCs), but its downstream targets are unclear. Here, we show for the first time that Gab1, an adaptor protein of receptor tyrosine kinase, is specifically expressed in OL lineage cells and is an essential effector of PDGF signaling in OPCs in mice. Gab1 is downregulated by PDGF stimulation and upregulated during OPC differentiation. Conditional deletions of in OLs cause CNS hypomyelination by affecting OPC differentiation. Moreover, Gab1 binds to downstream GSK3β and regulated its activity, and thereby affects the nuclear accumulation of β-catenin and the expression of a number of transcription factors critical to myelination. Our work uncovers a novel downstream target of PDGF signaling, which is essential to OPC differentiation and CNS myelination.

摘要

少突胶质细胞（OLs）包裹轴突，并为中枢神经系统（CNS）中的神经元提供电绝缘和营养支持。血小板衍生生长因子（PDGF）对少突胶质前体细胞（OPC）的稳态数量和分化至关重要，但下游靶标尚不清楚。在这里，我们首次表明，衔接蛋白 Gab1 是一种受体酪氨酸激酶的衔接蛋白，特异性表达于 OL 谱系细胞中，是 PDGF 信号在小鼠 OPC 中的必需效应物。PDGF 刺激下调 Gab1，而在 OPC 分化过程中上调。OL 中的条件性缺失会通过影响 OPC 分化导致 CNS 少突胶质化。此外，Gab1 与下游 GSK3β 结合并调节其活性，从而影响β-连环蛋白的核积累和许多对髓鞘形成至关重要的转录因子的表达。我们的工作揭示了 PDGF 信号的一个新的下游靶标，它对 OPC 分化和中枢神经系统髓鞘形成至关重要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e17/6984811/598e89aa1a05/elife-52056-resp-fig1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e17/6984811/598e89aa1a05/elife-52056-resp-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e17/6984811/b37999b0a70b/elife-52056-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e17/6984811/870b89afac7d/elife-52056-fig2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e17/6984811/c90cf5339294/elife-52056-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e17/6984811/29b6b6d4803b/elife-52056-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e17/6984811/62ceea42148f/elife-52056-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e17/6984811/023860db3f1b/elife-52056-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e17/6984811/5a3f3b853f87/elife-52056-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e17/6984811/6c2d17a53d1e/elife-52056-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e17/6984811/75eb9445d3d4/elife-52056-fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e17/6984811/93afa1adfd2b/elife-52056-fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4e17/6984811/598e89aa1a05/elife-52056-resp-fig1.jpg

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