Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation
Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation
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DOI：
10.1038/nature02060
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发表时间：
2003-10-30
期刊：
影响因子：
64.8
通讯作者：
Morrison, SJ
中科院分区：
文献类型：
--
作者：
Molofsky, AV;Pardal, R;Morrison, SJ
干细胞通过在包括中枢（1）和外周（2）神经系统在内的许多组织中自我更新而在整个生命过程中持续存在。这就提出了一个问题，即是否存在一种保守的机制来影响自我更新的分裂。polycomb家族转录抑制因子Bmi-1的缺陷导致进行性出生后生长迟缓和神经缺陷（3）。在这里，我们表明，Bmi-1是需要在外周和中枢神经系统的干细胞的自我更新，但不是为他们的生存或分化。缺乏Bmi-1的神经干细胞的自我更新减少导致其出生后耗尽。在缺乏Bmi-1的情况下，细胞周期蛋白依赖性激酶抑制剂基因p16（Ink 4a）在神经干细胞中上调，从而降低增殖速率。p16（Ink 4a）缺陷部分逆转Bmi-1（-/-）神经干细胞的自我更新缺陷Bmi-1促进自我更新和抑制p16（Ink 4a）表达的保守要求表明，一种共同的机制调节不同类型干细胞的自我更新和出生后的持久性。在缺乏Bmi-1的情况下，来自肠和前脑的受限神经祖细胞正常增殖。因此，Bmi-1依赖性将这些组织中的干细胞自我更新与受限制的祖细胞增殖区分开来。
Stem cells persist throughout life by self-renewing in numerous tissues including the central(1) and peripheral(2) nervous systems. This raises the issue of whether there is a conserved mechanism to effect self-renewing divisions. Deficiency in the polycomb family transcriptional repressor Bmi-1 leads to progressive postnatal growth retardation and neurological defects(3). Here we show that Bmi-1 is required for the self-renewal of stem cells in the peripheral and central nervous systems but not for their survival or differentiation. The reduced self-renewal of Bmi-1-deficient neural stem cells leads to their postnatal depletion. In the absence of Bmi-1, the cyclin-dependent kinase inhibitor gene p16(Ink4a) is upregulated in neural stem cells, reducing the rate of proliferation. p16(Ink4a) deficiency partially reverses the self-renewal defect in Bmi-1(-/-) neural stem cells. This conserved requirement for Bmi-1 to promote self-renewal and to repress p16(Ink4a) expression suggests that a common mechanism regulates the self-renewal and postnatal persistence of diverse types of stem cell. Restricted neural progenitors from the gut and forebrain proliferate normally in the absence of Bmi-1. Thus, Bmi-1 dependence distinguishes stem cell self-renewal from restricted progenitor proliferation in these tissues.