Primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by small brain size with mental retardation. CPAP (also known as CENPJ), a known microcephaly-associated 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 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 Cpap gene-deleted mice that lose only one allele of p53 (also known as Trp53), while simultaneous removal of p53 and Cpap rescues RGP death. Furthermore, Cpap 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.

原发性小头畸形 (MCPH) 是一种神经发育障碍，其特征是大脑体积小且智力低下。CPAP（也称为CENPJ）是一种已知的小头畸形相关基因，在中心粒生物发生中发挥着关键作用。在这里，我们在小鼠Cpap基因中生成了一个先前未报告的条件敲除等位基因。我们的结果表明，中枢神经系统中的条件性Cpap缺失优先诱导放射状胶质祖细胞 (RGP) 在胚胎第 14.5 天左右形成单极纺锤体，并导致强烈的细胞凋亡，严重破坏胚胎大脑。有趣的是，在条件性Cpap基因缺失小鼠中检测到细胞凋亡减少的小头脑，这些小鼠仅丢失p53的一个等位基因（也称为Trp53），而同时删除p53和Cpap可以挽救 RGP 死亡。此外，Cpap缺失会导致纤毛丢失、RGP 错位、连接完整性破坏、大量异位和严重小脑发育不全。总之，这些发现表明，CPAP 完全丧失会导致小鼠大脑发育中出现严重且复杂的表型，并为 MCPH 的病因提供新的见解。