p63 Antagonizes p53 to Promote the Survival of Embryonic Neural Precursor Cells
p63 Antagonizes p53 to Promote the Survival of Embryonic Neural Precursor Cells
复制标题
DOI：
10.1523/jneurosci.5878-08.2009
复制
发表时间：
2009-05-20
影响因子：
5.3
通讯作者：
Miller, Freda D.
中科院分区：
文献类型：
--
作者：
Dugani, Chandrasagar B.;Paquin, Annie;Miller, Freda D.
调控胚胎神经前体存活的分子机制仍然相对不明确。在这里，我们研究了p53家族成员p63是否在这一发育窗口期发挥作用，重点关注胚胎大脑皮层。我们发现p63的基因敲低无论是在培养中还是在胚胎端脑中都会导致皮质前体和新生皮质神经元的凋亡，而这可以通过表达Delta Np63而不是TAp63同种异构体来挽救。这种皮质前体细胞凋亡是p53活性失控的结果，因为基础前体细胞凋亡和p63缺失引起的细胞凋亡都可以通过p53的基因沉默得到恢复。最后，我们证明了p53家族的第三个成员Delta Np73不调节皮质前体细胞的存活，但它与Delta Np63协同确保新生皮质神经元的存活。因此，Delta Np63与p53的平衡决定了胚胎皮质前体的生死，这些p53家族成员可能在其他发育和/或成年神经前体群体中发挥着重要作用。
The molecular mechanisms that regulate survival of embryonic neural precursors are still relatively ill-defined. Here, we have asked whether the p53 family member p63 plays any role during this developmental window, focusing on the embryonic cerebral cortex. We show that genetic knockdown of p63 either in culture or in the embryonic telencephalon causes apoptosis of cortical precursors and newly born cortical neurons, and that this can be rescued by expression of Delta Np63, but not TAp63 isoforms. This cortical precursor apoptosis is the consequence of deregulated p53 activity, since both basal precursor apoptosis and that induced by loss of p63 are rescued by coincident genetic silencing of p53. Finally, we demonstrate that the third p53 family member, Delta Np73, does not regulate survival of cortical precursor cells, but that it collaborates with Delta Np63 to ensure the survival of newly born cortical neurons. Thus, the balance of Delta Np63 versus p53 determines the life versus death of embryonic cortical precursors, a role that these p53 family members may well play in other populations of developing and/or adult neural precursors.