An inhibition of cyclin-dependent kinases that lengthens, but does not arrest, neuroepithelial cell cycle induces premature neurogenesis
An inhibition of cyclin-dependent kinases that lengthens, but does not arrest, neuroepithelial cell cycle induces premature neurogenesis
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DOI：
10.1242/jcs.00825
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发表时间：
2003-12-15
影响因子：
4
通讯作者：
Huttner, WB
中科院分区：
文献类型：
--
作者：
Calegari, F;Huttner, WB
已知神经上皮细胞（哺乳动物中枢神经系统的所有神经元的祖细胞）的细胞周期的G1期随着神经发生的开始和进展而延长。我们已经研究了神经上皮细胞周期的G1期延长是否是神经发生的原因，而不是结果。作为一个实验系统，我们使用整个小鼠胚胎培养，这是发现，准确地再现发生在子宫内的神经发生的发病的时间和空间梯度。Olomoucine是一种细胞渗透性的、高度特异性的细胞周期蛋白依赖性激酶和G1期进展抑制剂，当以80 μ M使用时，发现其显著延长但不阻止神经上皮细胞的细胞周期。在全胚胎培养物中发育至胚胎第10.5天的胚胎第9.5天至第10.5天的小鼠胚胎的端脑神经上皮中，该奥洛莫辛处理诱导（i）TIS 21的过早上调，TIS 21是识别已经从增殖性分裂转变为神经元生成分裂的神经上皮细胞的标志物，和（ii）神经元的过早生成。我们的数据表明，延长G1可以单独足以诱导神经上皮细胞分化。我们提出了一个模型，将细胞命运决定因素和不对称细胞分裂的影响与细胞周期的长度联系起来。
The G1 phase of the cell cycle of neuroepithelial cells, the progenitors of all neurons of the mammalian central nervous system, has been known to lengthen concomitantly with the onset and progression of neurogenesis. We have investigated whether lengthening of the G1 phase of the neuroepithelial cell cycle is a cause, rather than a consequence, of neurogenesis. As an experimental system, we used whole mouse embryo culture, which was found to exactly reproduce the temporal and spatial gradients of the onset of neurogenesis occurring in utero. Olomoucine, a cell-permeable, highly specific inhibitor of cyclin-dependent kinases and G1 progression, was found to significantly lengthen, but not arrest, the cell cycle of neuroepithelial cells when used at 80 muM. This olomoucine treatment induced, in the telencephalic neuroepithelium of embryonic day 9.5 to 10.5 mouse embryos developing in whole embryo culture to embryonic day 10.5, (i) the premature up-regulation of TIS21, a marker identifying neuroepithelial cells that have switched from proliferative to neuron-generating divisions, and (ii) the premature generation of neurons. Our data indicate that lengthening G1 can alone be sufficient to induce neuroepithelial cell differentiation. We propose a model that links the effects of cell fate determinants and asymmetric cell division to the length of the cell cycle.