Cdc7 kinase is required for postnatal brain development

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.

Automated summary

By using Nestin-Cre, we generated mice with Cdc7 knockout in neural stem cells, which displayed severe growth retardation and impaired postnatal brain development. Cerebral cortical layer formation was impaired, while cell numbers remained unchanged. In the hypoplastic cerebellum, granule cell numbers were reduced, indicating that Cdc7 is necessary for DNA replication and cell proliferation of granule cells during mid embryonic stage. These findings demonstrate differential roles of Cdc7 in brain DNA replication/cell proliferation and suggest a potential additional role in cell migration during neural development.