Sox2 Acts in a Dose-Dependent Fashion to Regulate Proliferation of Cortical Progenitors
Sox2 Acts in a Dose-Dependent Fashion to Regulate Proliferation of Cortical Progenitors
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DOI：
10.1016/j.celrep.2014.11.013
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发表时间：
2014-12-11
期刊：
影响因子：
8.8
通讯作者：
Muhr, Jonas
中科院分区：
文献类型：
--
作者：
Hagey, Daniel W.;Muhr, Jonas
器官的形成和维持依赖于缓慢自我更新的干细胞，这些干细胞为快速分裂的祖细胞提供中间群体，但这种增殖层次是如何调控的尚不清楚。通过在大脑皮层进行全基因组范围的单细胞和功能分析，我们证明了SOX2表达减少是干细胞和快速分裂的祖细胞之间过渡的关键调控信号。在干细胞中，Sox2高水平表达，这使得它能够抑制促增殖基因，其中Cyclin D1是最有效的靶点。SOX2通过与低亲和力基序结合来赋予这一功能，低亲和力基序促进Gro/Tle辅阻遏子与Tcf/Lef蛋白的协同招募。在分化过程中，神经因子减少Sox2的表达，从而降低Cyclin D1的表达，促进细胞增殖。我们的结果表明，不同亲和力的DNA基序的浓度依赖的Sox2的占据如何转化为抑制复合体的招募，从而调节神经干细胞和祖细胞的增殖动力学。
Organ formation and maintenance depends on slowly self-renewing stem cells that supply an intermediate population of rapidly dividing progenitors, but how this proliferative hierarchy is regulated is unknown. By performing genome-wide single-cell and functional analyses in the cortex, we demonstrate that reduced Sox2 expression is a key regulatory signature of the transition between stem cells and rapidly dividing progenitors. In stem cells, Sox2 is expressed at high levels, which enables its repression of proproliferative genes, of which Cyclin D1 is the most potent target. Sox2 confers this function through binding to low-affinity motifs, which facilitate the recruitment of Gro/Tle corepressors in synergy with Tcf/Lef proteins. Upon differentiation, proneural factors reduce Sox2 expression, which derepresses Cyclin D1 and promotes proliferation. Our results show how concentration-dependent Sox2 occupancy of DNA motifs of varying affinities translates into recruitment of repressive complexes, which regulate the proliferative dynamics of neural stem and progenitor cells.