Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation
Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation
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DOI：
10.1242/dev.01436
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发表时间：
2004-11-01
期刊：
影响因子：
4.6
通讯作者：
Kageyama, R
中科院分区：
文献类型：
--
作者：
Hatakeyama, J;Bessho, Y;Kageyama, R
放射状胶质细胞来源于神经上皮细胞，这两种类型的细胞都被鉴定为神经干细胞。众所周知，神经干细胞在发育过程中会随着时间的推移而改变其能力：它们最初只进行自我更新，然后首先形成神经元，然后形成神经胶质细胞。因此，维持神经干细胞到晚期对于产生数量正确和类型多样的细胞是必不可少的，但人们对细胞分化的时机是如何调节的，以及细胞分化的放松如何影响脑器官发生知之甚少。在这里，我们报告了已知的Notch效应器Hes1和Hes5的失活以及Hes3的额外失活广泛地加速了细胞分化，并导致了广泛的脑形成缺陷。在Hes缺陷的胚胎中，最初形成的神经上皮细胞没有得到适当的维持，放射状胶质细胞过早分化为神经元，并在没有产生晚出生细胞的情况下枯竭。此外，放射状胶质细胞的丢失破坏了神经管的内外屏障，扰乱了组织发生。此外，前脑缺乏视泡和神经节隆起。因此，Hes基因通过控制细胞分化的时机，对于产生合适的大小、形状和细胞排列的大脑结构是必不可少的。我们的数据还表明，胚胎神经干细胞随着时间的推移而改变其特征的顺序如下：HES非依赖的神经上皮细胞，短暂的HES依赖的神经上皮细胞和HES依赖的放射状胶质细胞。
Radial glial cells derive from neuroepithelial cells, and both cell types are identified as neural stem cells. Neural stem cells are known to change their competency over time during development: they initially undergo self-renewal only and then give rise to neurons first and glial cells later. Maintenance of neural stem cells until late stages is thus believed to be essential for generation of cells in correct numbers and diverse types, but little is known about how the timing of cell differentiation is regulated and how its deregulation influences brain organogenesis. Here, we report that inactivation of Hes1 and Hes5, known Notch effectors, and additional inactivation of Hes3 extensively accelerate cell differentiation and cause a wide range of defects in brain formation. In Hes-deficient embryos, initially formed neuroepithelial cells are not properly maintained, and radial glial cells are prematurely differentiated into neurons and depleted without generation of late-born cells. Furthermore, loss of radial glia disrupts the inner and outer barriers of the neural tube, disorganizing the histogenesis. In addition, the forebrain lacks the optic vesicles and the ganglionic eminences. Thus, Hes genes are essential for generation of brain structures of appropriate size, shape and cell arrangement by controlling the timing of cell differentiation. Our data also indicate that embryonic neural stem cells change their characters over time in the following order: Hes-independent neuroepithelial cells, transitory Hes-dependent neuroepithelial cells and Hesdependent radial glial cells.