Insolera Ryan, Bazzi Hisham, Shao Wei, Anderson Kathryn V, Shi Song-Hai
1] Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Graduate Program in Neuroscience, Weill Cornell Medical College, New York, New York, USA. [3].
1] Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2].
Nat Neurosci. 2014 Nov;17(11):1528-35. doi: 10.1038/nn.3831. Epub 2014 Oct 5.
Neuronal production in the mammalian cortex depends on extensive mitoses of radial glial progenitors (RGPs) residing in the ventricular zone (VZ). We examined the function of centrioles in RGPs during cortical neurogenesis in mice by conditional removal of SAS-4, a protein that is required for centriole biogenesis. SAS-4 deletion led to a progressive loss of centrioles, accompanied by RGP detachment from the VZ. Delocalized RGPs did not become outer subventricular zone RGPs (oRGs). Although they remained proliferative, ectopic RGPs, as well as those in the VZ, with a centrosomal deficit exhibited prolonged mitosis, p53 upregulation and apoptosis, resulting in neuronal loss and microcephaly. Simultaneous removal of p53 fully rescued RGP death and microcephaly, but not RGP delocalization and randomized mitotic spindle orientation. Our findings define the functions of centrioles in anchoring RGPs in the VZ and ensuring their efficient mitoses, and reveal the robust adaptability of RGPs in the developing cortex.
哺乳动物皮质中的神经元生成依赖于位于脑室区(VZ)的放射状胶质祖细胞(RGP)的大量有丝分裂。我们通过条件性去除SAS-4(一种中心粒生物发生所需的蛋白质)来研究小鼠皮质神经发生过程中RGP中中心粒的功能。SAS-4缺失导致中心粒逐渐丢失,同时RGP从VZ脱离。异位的RGP并没有变成外侧脑室下区RGP(oRG)。尽管异位RGP以及VZ中的RGP仍然具有增殖能力,但中心体缺陷的它们表现出有丝分裂延长、p53上调和细胞凋亡,导致神经元丢失和小头畸形。同时去除p53完全挽救了RGP死亡和小头畸形,但没有挽救RGP脱离和有丝分裂纺锤体方向随机化的问题。我们的研究结果确定了中心粒在将RGP锚定在VZ并确保其高效有丝分裂中的功能,并揭示了发育中的皮质中RGP强大的适应性。