BACKGROUND During the development of the mammalian cerebral cortex, newborn postmitotic projection neurons are born from local neural stem cells and must undergo radial migration so as to position themselves appropriately to form functional neural circuits. The zinc finger transcriptional repressor Rp58 (also known as Znf238 or Zbtb18) is critical for coordinating corticogenesis, but its underlying molecular mechanism remains to be better characterised. FINDINGS Here, we demonstrate that the co-expression of Rp58 and the cyclin dependent kinase inhibitor (CDKI) p27kip1 is important for E14.5-born cortical neurons to coordinate cell cycle exit and initiate their radial migration. Notably, we find that the impaired radial positioning of Rp58-deficient cortical neurons within the embryonic (E17.5) mouse cortex, as well as their multipolar to bipolar transition from the intermediate zone to the cortical plate can be restored by forced expression of p27kip1 in concert with suppression of Rnd2, a downstream target gene of Rp58. Furthermore, the restorative effects of p27kip1 and Rnd2 abrogation are reminiscent of suppressing RhoA signalling in Rp58-deficient cells. CONCLUSIONS Our findings demonstrate functional interplay between a transcriptional regulator and a CDKI to mediate neuroprogenitor cell cycle exit, as well as to promote radial migration through a molecular mechanism consistent with suppression of RhoA signalling.

中文翻译：

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Rp58 和 p27kip1 协调胚胎小鼠大脑皮层内的细胞周期退出和神经元迁移。


背景技术在哺乳动物大脑皮层的发育过程中，新生的有丝分裂后投射神经元由局部神经干细胞产生，并且必须进行径向迁移，以便将自身定位在适当的位置以形成功能性神经回路。锌指转录抑制因子 Rp58（也称为 Znf238 或 Zbtb18）对于协调皮质生成至关重要，但其潜在的分子机制仍有待更好地表征。在此，我们证明 Rp58 和细胞周期蛋白依赖性激酶抑制剂 (CDKI) p27kip1 的共表达对于 E14.5 出生的皮质神经元协调细胞周期退出和启动其径向迁移非常重要。值得注意的是，我们发现胚胎（E17.5）小鼠皮质内 Rp58 缺陷的皮质神经元的径向定位受损，以及它们从中间区到皮质板的多极到双极的转变可以通过 p27kip1 的强制表达来恢复与 Rp58 下游靶基因 Rnd2 的抑制相一致。此外，p27kip1 和 Rnd2 废除的恢复作用让人想起抑制 Rp58 缺陷细胞中的 RhoA 信号传导。结论 我们的研究结果证明转录调节因子和 CDKI 之间的功能相互作用可介导神经祖细胞周期退出，并通过与抑制 RhoA 信号传导一致的分子机制促进径向迁移。