GATOR2 complex-mediated amino acid signaling regulates brain myelination.
GATOR2 complex-mediated amino acid signaling regulates brain myelination.
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GATOR 2复合物介导的氨基酸信号调节脑髓鞘形成。
DOI：
10.1073/pnas.2110917119
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发表时间：
2022-01-18
影响因子：
11.1
通讯作者：
Xiao B
中科院分区：
文献类型：
--
作者：
Yu Z;Yang Z;Ren G;Wang Y;Luo X;Zhu F;Yu S;Jia L;Chen M;Worley PF;Xiao B
神经冲动以能量效率沿着神经细胞的轴突的快速传输对于脑功能是必不可少的。为了实现这一目标，轴突被从少突胶质细胞延伸的髓鞘膜包裹，这被称为轴突的髓鞘形成。因此，髓鞘形成依赖于少突胶质细胞谱系细胞的形成。少突胶质细胞谱系是如何形成的仍不完全清楚。以往的研究表明，生长因子和氨基酸的信号通路可能协调调节少突胶质细胞的形成，但具体的氨基酸信号通路参与这一调节尚未确定。本研究鉴定了氨基酸信号传导复合物GATOR 2（GAP对Rags 2的活性）作为少突胶质细胞形成和髓鞘形成的正调节剂，其与生长因子信号传导协调调节脑髓鞘形成。氨基酸是细胞生长和新陈代谢所必需的。氨基酸和生长因子信号通路协同调节雷帕霉素复合物1（mTORC 1）激酶在细胞生长和器官发育中的机制靶点。虽然氨基酸信号传导机制的主要成分已被确定，但它们在器官发育中的生物学功能尚不清楚。我们的目的是了解关键位置的氨基酸信号复合物GAP活性对Rags 2（GATOR 2）在大脑发育中的功能。GATOR 2通过将精氨酸和亮氨酸的氨基酸传感器直接连接到下游信号复合物来介导mTORC 1的氨基酸信号传导。现在，我们报告GATOR 2在出生后大脑发育中的少突胶质细胞髓鞘形成中的作用。我们发现，通过基因缺失卵母细胞发育的减数分裂调节因子（米奥斯，编码GATOR 2的一个组分）来破坏GATOR 2复合物，选择性地损害髓鞘形成少突胶质细胞的形成，从而损害脑髓鞘形成，而对神经元和星形胶质细胞的形成没有明显影响。米奥斯的缺失损害了少突胶质细胞前体细胞的细胞周期进程，导致其增殖和分化降低。米奥斯缺失表现出对大脑中mTORC 1的细胞类型依赖性影响，少突胶质细胞mTORC 1选择性受到影响。然而，米奥斯/GATOR 2在少突胶质细胞形成和髓鞘形成中的作用涉及mTORC 1非依赖性功能。这项研究表明，GATOR 2协调氨基酸和生长因子信号，以调节少突胶质细胞髓鞘形成。
Fast transmission of nerve impulses with energetic efficiency along axons of nerve cells is essential for brain function. Toward this goal, axons are wrapped by the myelin membranes extended from oligodendrocytes, which is known as myelination of axons. Therefore, myelination is dependent on the formation of oligodendrocyte lineage cells. How the oligodendrocyte lineage is formed remains incompletely known. Previous studies suggest that signaling pathways of growth factors and amino acids might coordinate the regulation of oligodendrocyte formation, but the specific amino acid signaling pathway that participates in this regulation has not been identified. This study identifies the amino acid signaling complex GATOR2 (GAP activity towards Rags 2) as a positive regulator of oligodendrocyte formation and myelination that coordinately regulates brain myelination with growth factor signaling. Amino acids are essential for cell growth and metabolism. Amino acid and growth factor signaling pathways coordinately regulate the mechanistic target of rapamycin complex 1 (mTORC1) kinase in cell growth and organ development. While major components of amino acid signaling mechanisms have been identified, their biological functions in organ development are unclear. We aimed to understand the functions of the critically positioned amino acid signaling complex GAP activity towards Rags 2 (GATOR2) in brain development. GATOR2 mediates amino acid signaling to mTORC1 by directly linking the amino acid sensors for arginine and leucine to downstream signaling complexes. Now, we report a role of GATOR2 in oligodendrocyte myelination in postnatal brain development. We show that the disruption of GATOR2 complex by genetic deletion of meiosis regulator for oocyte development (Mios, encoding a component of GATOR2) selectively impairs the formation of myelinating oligodendrocytes, thus brain myelination, without apparent effects on the formation of neurons and astrocytes. The loss of Mios impairs cell cycle progression of oligodendrocyte precursor cells, leading to their reduced proliferation and differentiation. Mios deletion manifests a cell type–dependent effect on mTORC1 in the brain, with oligodendroglial mTORC1 selectively affected. However, the role of Mios/GATOR2 in oligodendrocyte formation and myelination involves mTORC1-independent function. This study suggests that GATOR2 coordinates amino acid and growth factor signaling to regulate oligodendrocyte myelination.
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影响因子：
8.8
作者：
Chantranupong L;Wolfson RL;Orozco JM;Saxton RA;Scaria SM;Bar-Peled L;Spooner E;Isasa M;Gygi SP;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
64.5
作者：
Demetriades C;Doumpas N;Teleman AA
通讯作者：
Teleman AA
影响因子：
5.3
作者：
Bercury, Kathryn K.;Dai, JinXiang;Macklin, Wendy B.
通讯作者：
Macklin, Wendy B.
影响因子：
5.7
作者：
Deoni S;Dean D 3rd;Joelson S;O'Regan J;Schneider N
通讯作者：
Schneider N
影响因子：
11.8
作者：
Hosios AM;Hecht VC;Danai LV;Johnson MO;Rathmell JC;Steinhauser ML;Manalis SR;Vander Heiden MG
通讯作者：
Vander Heiden MG