Lfc and Tctex-1 regulate the genesis of neurons from cortical precursor cells
Lfc and Tctex-1 regulate the genesis of neurons from cortical precursor cells
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DOI：
10.1038/nn.2339
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发表时间：
2009-06-01
影响因子：
25
通讯作者：
Miller, Freda D.
中科院分区：
文献类型：
--
作者：
Gauthier-Fisher, Andree;Lin, Dan C.;Miller, Freda D.
哺乳动物神经前体的对称性、增殖性分裂与不对称的神经源性分裂的调控机制仍不十分清楚。我们发现，LFC(Arhgef2)，一种与纺锤体微管相互作用的Rho特异性鸟嘌呤核苷酸交换因子，及其负调控因子Tctex-1(Dylt1)决定了小鼠胚胎皮质中前体神经元的发生。具体地说，无论是在培养中还是在体内，皮质前体细胞中Arhgef2的基因敲除都抑制了神经发生，并将细胞维持为循环的放射状前体细胞。相反，在放射状前体中，Dylt1的基因敲除促进了神经发生，并耗尽了循环的皮质前体。这两个基因的同时沉默表明，Tctex-1通常通过拮抗LFC的神经原性作用来抑制放射状前体神经元的发生。此外，LFC和Tctex-1还需要在体内确定有丝分裂前体细胞分裂的方向。因此，LFC和Tctex-1相互作用，可能通过调节有丝分裂纺锤体的方向来调节皮质神经发生。
The mechanisms that regulate symmetric, proliferative divisions versus asymmetric, neurogenic divisions of mammalian neural precursors are still not well understood. We found that Lfc (Arhgef2), a Rho-specific guanine nucleotide exchange factor that interacts with spindle microtubules, and its negative regulator Tctex-1 (Dynlt1) determine the genesis of neurons from precursors in the embryonic murine cortex. Specifically, genetic knockdown of Arhgef2 in cortical precursors either in culture or in vivo inhibited neurogenesis and maintained cells as cycling radial precursors. Conversely, genetic knockdown of Dynlt1 in radial precursors promoted neurogenesis and depleted cycling cortical precursors. Coincident silencing of these two genes indicated that Tctex-1 normally inhibits the genesis of neurons from radial precursors by antagonizing the proneurogenic actions of Lfc. Moreover, Lfc and Tctex-1 were required to determine the orientation of mitotic precursor cell divisions in vivo. Thus, Lfc and Tctex-1 interact to regulate cortical neurogenesis, potentially by regulating mitotic spindle orientation.