ABSTRACT
Development of the cerebral cortex requires precise divisions of neural stem cells (NSCs) that undergo symmetric and asymmetric divisions to produce post-mitotic neurons. One consequence of impaired embryonic NSC proliferation is microcephaly, or a small brain. Errors in NSC division are a common mechanism for microcephaly, resulting in slower proliferation, changes in cell fates, and/or cell death. While programmed cell death, or apoptosis, is increased in many mouse models of microcephaly, the mechanisms that control cell survival in NSCs are still not well understood. In a novel mouse model for microcephaly discovered by our lab, the mutation of the kinesin Kif20b results in reduced brain size at birth. Kif20b, previously known as Mphosph1, Mpp1 or KRMP1, regulates the last step of cytokinesis, abscission. After cleavage furrowing, the central spindle is compacted into the midbody, the last connection between two cells before the final separation, abscission. Midbody abnormalities and increased apoptosis were noted in Kif20b−/− embryonic brains. However, it was not known whether apoptosis was causative for the microcephaly, and whether it was a cell autonomous consequence of Kif20b loss in NSCs. To ascertain the contribution of apoptosis to Kif20b−/− microcephaly, we crossed the Kif20b mutant mouse to knockouts for the pro-apoptotic genes Trp53 (encoding the tumor suppressor p53) and Bax to produce double mutants. We found that Bax deletion only partially rescues, but p53 deletion fully rescues the embryonic apoptosis and microcephaly in Kif20b mutants. Interestingly, heterozygous deletion of p53 provided the same amount of rescue as homozygous p53 deletion. Finally, we demonstrated that midbody defects and apoptosis are both cell-autonomous consequences of Kif20b loss in NSCs. Thus, p53-dependent apoptosis in embryonic NSCs is the cause of microcephaly in Kif20b−/− mice. This adds to a growing body of evidence that p53 regulates cell survival decisions in embryonic NSCs, and also suggests that p53 responds to cytokinetic abscission defects in addition to other cell cycle defects. Future work will focus on determining the relationship between cytokinesis defects and p53 activation in Kif20b−/− mice and the consequences of abscission defects in Kif20b−/− p53−/− mice.