Banting and Best Department of Medical Research, Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
Mol Cell. 2011 Sep 2;43(5):843-50. doi: 10.1016/j.molcel.2011.08.014.
Neurogenesis requires the concerted action of numerous genes that are regulated at multiple levels. However, how different layers of gene regulation are coordinated to promote neurogenesis is not well understood. We show that the neural-specific Ser/Arg repeat-related protein of 100 kDa (nSR100/SRRM4) negatively regulates REST (NRSF), a transcriptional repressor of genes required for neurogenesis. nSR100 directly promotes alternative splicing of REST transcripts to produce a REST isoform (REST4) with greatly reduced repressive activity, thereby activating expression of REST targets in neural cells. Conversely, REST directly represses nSR100 in nonneural cells to prevent the activation of neural-specific splicing events. Consistent with a critical role for nSR100 in the inhibition of REST activity, blocking nSR100 expression in the developing mouse brain impairs neurogenesis. Our results thus reveal a fundamental role for direct regulatory interactions between a splicing activator and transcription repressor in the control of the multilayered regulatory programs required for neurogenesis.
神经发生需要许多基因的协同作用，这些基因在多个水平上受到调节。然而，不同层次的基因调控如何协调以促进神经发生还不是很清楚。我们发现，100kDa 的神经特异性丝氨酸/精氨酸重复相关蛋白(nSR100/SRRM4)负调节 REST（NRSF），REST 是神经发生所需基因的转录抑制剂。nSR100 直接促进 REST 转录本的可变剪接，产生一种抑制活性大大降低的 REST 同工型（REST4），从而激活神经细胞中 REST 靶基因的表达。相反，REST 直接在非神经细胞中抑制 nSR100，以防止神经特异性剪接事件的激活。nSR100 在阻止 REST 活性中的关键作用与在发育中的小鼠大脑中阻断 nSR100 表达会损害神经发生的结果一致。因此，我们的研究结果揭示了剪接激活因子和转录抑制因子之间直接的调控相互作用在控制神经发生所需的多层次调控程序中的基本作用。
