Morimoto-Suzki Nao, Hirabayashi Yusuke, Tyssowski Kelsey, Shinga Jun, Vidal Miguel, Koseki Haruhiko, Gotoh Yukiko
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan
Development. 2014 Nov;141(22):4343-53. doi: 10.1242/dev.112276. Epub 2014 Oct 24.
In the developing neocortex, neural precursor cells (NPCs) sequentially generate various neuronal subtypes in a defined order. Although the precise timing of the NPC fate switches is essential for determining the number of neurons of each subtype and for precisely generating the cortical layer structure, the molecular mechanisms underlying these switches are largely unknown. Here, we show that epigenetic regulation through Ring1B, an essential component of polycomb group (PcG) complex proteins, plays a key role in terminating NPC-mediated production of subcerebral projection neurons (SCPNs). The level of histone H3 residue K27 trimethylation at and Ring1B binding to the promoter of Fezf2, a fate determinant of SCPNs, increased in NPCs as Fezf2 expression decreased. Moreover, deletion of Ring1B in NPCs, but not in postmitotic neurons, prolonged the expression of Fezf2 and the generation of SCPNs that were positive for CTIP2. These results indicate that Ring1B mediates the timed termination of Fezf2 expression and thereby regulates the number of SCPNs.
在发育中的新皮层中，神经前体细胞（NPCs）按特定顺序依次产生各种神经元亚型。尽管NPC命运转换的精确时间对于确定每种亚型神经元的数量以及精确形成皮质层结构至关重要，但这些转换背后的分子机制在很大程度上仍不清楚。在此，我们表明通过Ring1B进行的表观遗传调控在终止NPC介导的大脑下投射神经元（SCPNs）产生中起关键作用，Ring1B是多梳蛋白家族（PcG）复合蛋白的一个重要组成部分。随着Fezf2表达降低，NPC中Fezf2启动子处组蛋白H3残基K27三甲基化水平以及Ring1B与Fezf2启动子的结合增加，Fezf2是SCPNs的命运决定因子。此外，在NPC中而非有丝分裂后神经元中缺失Ring1B，会延长Fezf2的表达以及CTIP2阳性的SCPNs的产生。这些结果表明，Ring1B介导Fezf2表达的定时终止，从而调节SCPNs的数量。
