Zencak Dusan, Lingbeek Merel, Kostic Corinne, Tekaya Meriem, Tanger Ellen, Hornfeld Dana, Jaquet Muriel, Munier Francis L, Schorderet Daniel F, van Lohuizen Maarten, Arsenijevic Yvan
Jules Gonin Eye Hospital, Department of Ophthalmology, Lausanne University Medical School, 1004 Lausanne, Switzerland.
J Neurosci. 2005 Jun 15;25(24):5774-83. doi: 10.1523/JNEUROSCI.3452-04.2005.
The polycomb transcriptional repressor Bmi1 promotes cell cycle progression, controls cell senescence, and is implicated in brain development. Loss of Bmi1 leads to a decreased brain size and causes progressive ataxia and epilepsy. Recently, Bmi1 was shown to control neural stem cell (NSC) renewal. However, the effect of Bmi1 loss on neural cell fate in vivo and the question whether the action of Bmi1 was intrinsic to the NSCs remained to be investigated. Here, we show that Bmi1 is expressed in the germinal zone in vivo and in NSCs as well as in progenitors proliferating in vitro, but not in differentiated cells. Loss of Bmi1 led to a decrease in proliferation in zones known to contain progenitors: the newborn cortex and the newborn and adult subventricular zone. This decrease was accentuated in vitro, where we observed a drastic reduction in NSC proliferation and renewal because of NSC-intrinsic effects of Bmi1 as shown by the means of RNA interference. Bmi1(-/-) mice also presented more astrocytes at birth, and a generalized gliosis at postnatal day 30. At both stages, colocalization of bromodeoxyuridine and GFAP demonstrated that Bmi1 loss did not prevent astrocyte precursor proliferation. Supporting these observations, Bmi1(-/-) neurospheres generate preferentially astrocytes probably attributable to a different responsiveness to environmental factors. Bmi1 is therefore necessary for NSC renewal in a cell-intrinsic mode, whereas the altered cell pattern of the Bmi1(-/-) brain shows that in vivo astrocyte precursors can proliferate in the absence of Bmi1.
多梳转录抑制因子Bmi1可促进细胞周期进程，控制细胞衰老，并与大脑发育有关。Bmi1缺失会导致脑体积减小，并引起进行性共济失调和癫痫。最近研究表明，Bmi1可控制神经干细胞（NSC）的更新。然而，Bmi1缺失对体内神经细胞命运的影响以及Bmi1的作用是否对神经干细胞具有内在性这一问题仍有待研究。在此，我们发现Bmi1在体内生发区、神经干细胞以及体外增殖的祖细胞中表达，但在分化细胞中不表达。Bmi1缺失导致已知含有祖细胞的区域（新生皮质以及新生和成年脑室下区）增殖减少。在体外这种减少更为明显，通过RNA干扰手段我们观察到由于Bmi1对神经干细胞的内在作用，神经干细胞的增殖和更新急剧减少。Bmi1(-/-)小鼠出生时也出现更多星形胶质细胞，在出生后第30天出现广泛的胶质增生。在这两个阶段，溴脱氧尿苷与胶质纤维酸性蛋白（GFAP）的共定位表明Bmi1缺失并不阻止星形胶质细胞前体的增殖。支持这些观察结果的是，Bmi1(-/-)神经球可能由于对环境因子的不同反应性而优先产生星形胶质细胞。因此，Bmi1以细胞内在模式对神经干细胞更新是必需的，而Bmi1(-/-)大脑中改变的细胞模式表明，在体内星形胶质细胞前体在没有Bmi1的情况下也可以增殖。
