Jmy regulates oligodendrocyte differentiation via modulation of actin cytoskeleton dynamics
Jmy regulates oligodendrocyte differentiation via modulation of actin cytoskeleton dynamics
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DOI：
10.1002/glia.23342
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发表时间：
2018-09-01
期刊：
影响因子：
6.2
通讯作者：
Relvas, Joao B.
中科院分区：
文献类型：
--
作者：
Azevedo, Maria M.;Domingues, Helena S.;Relvas, Joao B.
在中枢神经系统发育过程中，少突胶质细胞形成结构和功能独特的富含肌动蛋白的突起，这些突起与轴突接触并包裹在轴突周围，形成髓鞘。轴突接触的建立是髓鞘形成的一个限制步骤，它依赖于少突胶质细胞在转录分化程序的控制下局部协调细胞骨架重排与髓鞘生成的能力。在少突胶质细胞分化和轴突嵌套过程中提供肌动蛋白动力学微调的分子在很大程度上仍未确定。我们对大鼠脑少突胶质祖细胞的体细胞和突起部分进行了转录组学分析，发现在新形成的突起中有mrna的亚细胞富集。大约30%的富集突起转录本编码与细胞骨架动力学相关的蛋白质，包括连接介导和调节蛋白Jmy，一种肌动蛋白聚合的多功能调节剂。在这里，我们发现Jmy的表达在髓鞘形成过程中被上调，并且是在少突胶质细胞分化过程中肌动蛋白丝的组装和突起形成所必需的。活体少突胶质细胞的定量形态动力学分析表明，分化是由典型的肌动蛋白网络依赖的“细胞塑造”程序驱动的。通过敲低Jmy破坏肌动蛋白动力学导致程序失败，导致少突胶质细胞不能获得树突形态，并且在与神经元共培养中接触神经突和形成髓鞘膜的效率较低。我们的发现为细胞形态动力学和发育分化之间的关系提供了新的机制见解。
During central nervous system development, oligodendrocytes form structurally and functionally distinct actin-rich protrusions that contact and wrap around axons to assemble myelin sheaths. Establishment of axonal contact is a limiting step in myelination that relies on the oligodendrocyte's ability to locally coordinate cytoskeletal rearrangements with myelin production, under the control of a transcriptional differentiation program. The molecules that provide fine-tuning of actin dynamics during oligodendrocyte differentiation and axon ensheathment remain largely unidentified. We performed transcriptomics analysis of soma and protrusion fractions from rat brain oligodendrocyte progenitors and found a subcellular enrichment of mRNAs in newly-formed protrusions. Approximately 30% of protrusion-enriched transcripts encode proteins related to cytoskeleton dynamics, including the junction mediating and regulatory protein Jmy, a multifunctional regulator of actin polymerization. Here, we show that expression of Jmy is upregulated during myelination and is required for the assembly of actin filaments and protrusion formation during oligodendrocyte differentiation. Quantitative morphodynamics analysis of live oligodendrocytes showed that differentiation is driven by a stereotypical actin network-dependent "cellular shaping" program. Disruption of actin dynamics via knockdown of Jmy leads to a program fail resulting in oligodendrocytes that do not acquire an arborized morphology and are less efficient in contacting neurites and forming myelin wraps in co-cultures with neurons. Our findings provide new mechanistic insight into the relationship between cell shape dynamics and differentiation in development.