Primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by small brain size with mental retardation. CPAP/CENPJ, a known microcephaly gene, plays a key role in centriole biogenesis. Here, we generated a previously unreported conditional knockout allele in the mouse Cpap gene. Our results showed that conditional Cpap deletion preferentially induces formation of monopolar spindles in radial glia progenitors (RGPs) and causes robust apoptosis that severely disrupts embryonic brains. Interestingly, microcephalic brains with reduced apoptosis are detected in the conditional Cpap gene-deleted mice, which lose only one allele of p53, while simultaneous removal of p53 and Cpap rescues RGPs death. Furthermore, Cpap deletion leads to cilia loss, RGPs mislocalization, junctional integrity disruption, massive heterotopia, and severe cerebellar hypoplasia. Together, these findings indicate that complete CPAP loss leads to severe and complex phenotypes in developing mouse brain, and provide new insights into the causes of MCPH.