Oscillatory expression of Hes1 regulates cell proliferation and neuronal differentiation in the embryonic brain
Oscillatory expression of Hes1 regulates cell proliferation and neuronal differentiation in the embryonic brain
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DOI：
10.1242/dev.182204
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发表时间：
2020-02-01
期刊：
影响因子：
4.6
通讯作者：
Kageyama, Ryoichiro
中科院分区：
文献类型：
--
作者：
Ochi, Shohei;Imaizura, Yui;Kageyama, Ryoichiro
转录抑制因子Hes1的表达在许多细胞类型中振荡，包括神经祖细胞（npc），但Hes1振荡在发育中的意义尚不完全清楚。为了研究Hes1振荡动力学改变的影响，我们产生了两种Hes1敲入小鼠，缩短（1型）和延长（2型）Hes1基因，并研究了它们的表型，重点是神经发育。虽然这两种突变都影响Hes1振荡，但1型突变对Hes1振荡的抑制更严重，导致振幅低得多。1型突变npc中Hes1的平均表达水平也低于野生型npc，但与Hes1杂合突变小鼠相近或略高，无明显缺陷。2型突变小鼠表现正常，而1型突变小鼠表现出比野生型小鼠更小的大脑，并且前神经基因表达上调。此外，在1型突变胚胎中，npc的增殖减少，细胞死亡增加。当Hes3和Hes5基因进一步缺失时，神经元分化也加快，导致小头畸形。因此，强大的Hes1振荡对于npc的维持和增殖以及神经发生的正常时间是必需的，从而调节脑形态发生。
The expression of the transcriptional repressor Hes1 oscillates in many cell types, including neural progenitor cells (NPCs), but the significance of Hes1 oscillations in development is not fully understood. To examine the effect of altered oscillatory dynamics of Hes1, we generated two types of Hes1 knock-in mice, a shortened (type-1) and an elongated (type-2)Hes1 gene, and examined their phenotypes focusing on neural development. Although both mutations affected Hes1 oscillations, the type-1 mutation dampened Hes1 oscillations more severely, resulting in much lower amplitudes. The average levels of Hes1 expression in type-1 mutant NPCs were also lower than in wild-type NPCs but similar to or slightly higher than those in Hes1 heterozygous mutant mice, which exhibit no apparent defects. Whereas type-2 mutant mice were apparently normal, type-1 mutant mice displayed smaller brains than wild-type mice and upregulated proneural gene expression. Furthermore, proliferation of NPCs decreased and cell death increased in type-1 mutant embryos. When Hes3 and Hes5 were additionally deleted, neuronal differentiation was also accelerated, leading to microcephaly. Thus, robust Hes1 oscillations are required for maintenance and proliferation of NPCs and the normal timing of neurogenesis, thereby regulating brain morphogenesis.