p53 deletion rescues apoptosis and microcephaly in a Kif20b mouse mutant
Building a cerebral cortex of the proper size involves balancing rates and timing of neural stem cell (NSC) proliferation, neurogenesis, and cell death. The cellular mechanisms connecting genetic mutations to brain malformation phenotypes are still poorly understood. Microcephaly may result when NSC divisions are too slow, produce neurons too early, or undergo apoptosis, but the relative contributions of these cellular mechanisms to various types of microcephaly are not understood. We previously showed that mouse mutants in Kif20b (formerly called Mphosph1, Mpp1, or KRMP1) have small cortices that show elevated apoptosis, and defects in maturation of NSC midbodies, which mediate cytokinetic abscission. Here we test the contribution of intrinsic NSC apoptosis to brain size reduction in this lethal microcephaly model. By making double mutants with the pro-apoptotic genes Bax and Trp53 (p53), we find that apoptosis of cortical NSCs accounts for most of the microcephaly, but that there is a significant apoptosis-independent contribution as well. Remarkably, heterozygous p53 deletion is sufficient to fully rescue survival of the Kif20b mutant into adulthood. In addition, the NSC midbody maturation defects are not rescued by p53 deletion, showing that they are either upstream of p53 activation, or in a parallel pathway. Thus, this work potentially identifies a novel midbody-mediated pathway for p53 activation, and elucidates both NSC apoptosis and abscission mechanisms that could underlie human microcephaly or other brain malformations.