Loss of CPAP in developing mouse brain and its functional implication for human primary microcephaly

Abstract

Primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by small brain size with mental retardation. <i>CPAP</i> (also known as <i>CENPJ</i>), a known microcephaly-associated gene, plays a key role in centriole biogenesis. Here, we generated a previously unreported conditional knockout allele in the mouse <i>Cpap</i> gene. Our results showed that conditional <i>Cpap</i> deletion in the central nervous system preferentially induces formation of monopolar spindles in radial glia progenitors (RGPs) at around embryonic day 14.5 and causes robust apoptosis that severely disrupts embryonic brains. Interestingly, microcephalic brains with reduced apoptosis are detected in conditional <i>Cpap</i> gene-deleted mice that lose only one allele of <i>p53</i> (also known as <i>Trp53</i>), while simultaneous removal of <i>p53</i> and <i>Cpap</i> rescues RGP death. Furthermore, <i>Cpap</i> deletion leads to cilia loss, RGP 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.