The evolutionally conserved Cdc7 kinase plays crucial roles in initiation of DNA replication as well as in other chromosomal events. To examine the roles of Cdc7 in brain development, we have generated mice carrying Cdc7 knockout in neural stem cells by using Nestin-Cre. The Cdc7^Fl/Fl Nestin^Cre mice were born, but exhibited severe growth retardation and impaired postnatal brain development. These mice exhibited motor dysfunction within 9 days after birth and did not survive for more than 19 days. The cerebral cortical layer formation was impaired, although the cortical cell numbers were not altered in the mutant. In the cerebellum undergoing hypoplasia, granule cells (CGC) decreased in number in Cdc7^{Fl/F l}Nestin^Cre mice compared to the control at E15-18, suggesting that Cdc7 is required for DNA replication and cell proliferation of CGC at mid embryonic stage (before embryonic day 15). On the other hand, the Purkinje cell numbers were not altered but its layer formation was impaired in the mutant. These results indicate differential roles of Cdc7 in DNA replication/cell proliferation in brain. Furthermore, the defects of layer formation suggest a possibility that Cdc7 may play an additional role in cell migration during neural development.

中文翻译：

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Cdc7 激酶是出生后大脑发育所必需的

进化上保守的 Cdc7 激酶在 DNA 复制启动以及其他染色体事件中发挥着至关重要的作用。为了研究 Cdc7 在大脑发育中的作用，我们使用 Nestin-Cre 培育了神经干细胞中携带 Cdc7 敲除的小鼠。Cdc7 ^Fl/Fl Nestin ^Cre小鼠出生后，但表现出严重的生长迟缓和出生后大脑发育受损。这些小鼠在出生后9天内就表现出运动功能障碍，并且存活时间不超过19天。尽管突变体中的皮质细胞数量没有改变，但大脑皮质层的形成受到损害。在发育不全的小脑中，与 E15-18 的对照相比，Cdc7 ^Fl/Fl Nestin ^Cre小鼠的颗粒细胞 (CGC) 数量减少，表明 Cdc7 是胚胎中期 CGC 的 DNA 复制和细胞增殖所必需的。胚胎第 15 天之前）。另一方面，突变体中浦肯野细胞数量没有改变，但其细胞层形成受到损害。这些结果表明 Cdc7 在大脑 DNA 复制/细胞增殖中的不同作用。此外，层形成的缺陷表明 Cdc7 可能在神经发育过程中的细胞迁移中发挥额外作用。