Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells
Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells
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DOI：
10.1073/pnas.0604066103
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发表时间：
2006-07-05
影响因子：
11.1
通讯作者：
Huttner, Wieland B.
中科院分区：
文献类型：
--
作者：
Fish, Jennifer L.;Kosodo, Yoichi;Huttner, Wieland B.
异常纺锤样小头症相关蛋白（异常纺锤样小头症相关蛋白）先前被认为与人类大脑皮质大小的决定有关，但这种调节的细胞生物学基础尚未被研究。在这里，我们研究了Aspm在小鼠胚胎神经上皮细胞（NE）中的作用，这是哺乳动物大脑的原代干细胞和祖细胞。Aspm被发现集中在NE细胞有丝分裂纺锤极，并随着它们从增殖分裂到神经原性分裂的转变而下调。在远脑NE细胞受到RNA干扰后，Aspm mRNA减少，有丝分裂纺锤极缺乏Aspm蛋白，NE细胞的卵裂面较少垂直于神经上皮的心室表面。NE细胞劈裂面方向的改变增加了这些高度极化细胞进行不对称分裂的可能性，即顶质膜仅由一个子细胞遗传。随着心室区腹侧细胞的增加，在神经元层发现了更大比例的NE祖细胞，这意味着Aspm敲除后NE祖细胞的数量相对于对照组减少。我们的研究结果表明，Aspm对于维持脑发育过程中NE细胞的对称增殖分裂的卵裂面方向至关重要。这些数据为在ASPM突变的人类中观察到的原发性小头畸形提供了细胞生物学解释，这也对哺乳动物大脑的进化有影响。
The ASPM (abnormal spindle-like microcephaly-associated) protein has previously been implicated in the determination of human cerebral cortical size, but the cell biological basis of this regulation has not been studied. Here we investigate the role of Aspm in mouse embryonic neuroepithelial (NE) cells, the primary stem and progenitor cells of the mammalian brain. Aspm was found to be concentrated at mitotic spindle poles of NE cells and to be down-regulated with their switch from proliferative to neurogenic divisions. Upon RNA interference in telencephalic NE cells, Aspm mRNA is reduced, mitotic spindle poles lack Aspm protein, and the cleavage plane of NE cells is less frequently oriented perpendicular to the ventricular surface of the neuroepithelium. The alteration in the cleavage plane orientation of NE cells increases the probability that these highly polarized cells undergo asymmetric division, i.e., that apical plasma membrane is inherited by only one of the daughter cells. Concomitant with the resulting increase in abventricular cells in the ventricular zone, a larger proportion of NE cell progeny is found in the neuronal layer, implying a reduction in the number of NE progenitor cells upon Aspm knock-down relative to control. Our results demonstrate that Aspm is crucial for maintaining a cleavage plane orientation that allows symmetric, proliferative divisions of NE cells during brain development. These data provide a cell biological explanation of the primary microcephaly observed in humans with mutations in ASPM, which also has implications for the evolution of mammalian brains.