The role of Pax6 in regulating the orientation and mode of cell division of progenitors in the mouse cerebral cortex
The role of Pax6 in regulating the orientation and mode of cell division of progenitors in the mouse cerebral cortex
复制标题
DOI：
10.1242/dev.074591
复制
发表时间：
2011-12-01
期刊：
影响因子：
4.6
通讯作者：
Goetz, Magdalena
中科院分区：
文献类型：
--
作者：
Asami, Maki;Pilz, Gregor A.;Goetz, Magdalena
成功的大脑发育需要严格调控连续的对称和不对称细胞分裂。虽然已知Pax 6在发育中的神经系统中发挥多种作用，但其在细胞分裂调节中的作用尚不清楚。在这里，我们展示了深刻的改变，在大脑皮层的细胞分裂的方向和模式的小鼠缺乏Pax 6功能（Pax 6Sey/Sey）或急性诱导缺失Pax 6。实时成像显示非垂直细胞分裂平面的增加，导致在Pax 6功能缺失的情况下，具有顶端膜结构域和粘附连接的不平等遗传的祖细胞数量增加。这种表型似乎是由直接的Pax 6靶点Spag 5（一种微管相关蛋白）介导的，其水平降低会导致细胞分裂方向改变的Pax 6表型的复制。此外，Pax 6的缺乏还导致祖细胞从心尖表面过早分层，这是由于介导心室表面锚定的蛋白质的总体减少。此外，体外连续长期成像显示，Pax 6缺陷的祖细胞以更高的频率产生具有不对称命运的子细胞。这些数据表明，细胞自主的作用Pax 6在调节细胞分裂模式独立的apicobasal极性和细胞-细胞相互作用。总之，我们的工作揭示了转录因子Pax 6对介导细胞分裂方向和模式的机制的几种直接影响。
Successful brain development requires tight regulation of sequential symmetric and asymmetric cell division. Although Pax6 is known to exert multiple roles in the developing nervous system, its role in the regulation of cell division is unknown. Here, we demonstrate profound alterations in the orientation and mode of cell division in the cerebral cortex of mice deficient in Pax6 function (Pax6Sey/Sey) or after acute induced deletion of Pax6. Live imaging revealed an increase in non-vertical cellular cleavage planes, resulting in an increased number of progenitors with unequal inheritance of the apical membrane domain and adherens junctions in the absence of Pax6 function. This phenotype appears to be mediated by the direct Pax6 target Spag5, a microtubule-associated protein, reduced levels of which result in the replication of the Pax6 phenotype of altered cell division orientation. In addition, lack of Pax6 also results in premature delamination of progenitor cells from the apical surface due to an overall decrease in proteins mediating anchoring at the ventricular surface. Moreover, continuous long-term imaging in vitro revealed that Pax6-deficient progenitors generate daughter cells with asymmetric fates at higher frequencies. These data demonstrate a cell-autonomous role for Pax6 in regulating the mode of cell division independently of apicobasal polarity and cell-cell interactions. Taken together, our work reveals several direct effects that the transcription factor Pax6 has on the machinery that mediates the orientation and mode of cell division.