Abstract：
Mutations in human nonsense-mediated mRNA decay (NMD) factors are enriched in neurodevelopmental disorders. We show that deletion of key NMD factor Upf2 in mouse embryonic neural progenitor cells causes perinatal microcephaly but deletion in immature neurons does not, indicating NMD\'s critical roles in progenitors. Upf2 knockout (KO) prolongs the cell cycle of radial glia progenitor cells, promotes their transition into intermediate progenitors, and leads to reduced upper-layer neurons. CRISPRi screening identified Trp53 knockdown rescuing Upf2KO progenitors without globally reversing NMD inhibition, implying marginal contributions of most NMD targets to the cell cycle defect. Integrated functional genomics shows that NMD degrades selective TRP53 downstream targets, including Cdkn1a, which, without NMD suppression, slow the cell cycle. Trp53KO restores the progenitor cell pool and rescues the microcephaly of Upf2KO mice. Therefore, one physiological role of NMD in the developing brain is to degrade selective TRP53 targets to control progenitor cell cycle and brain size.
摘要：
人类无义介导的mRNA衰变（NMD）因子的突变在神经发育障碍中富集。我们表明，小鼠胚胎神经祖细胞中关键NMD因子Upf2的缺失会导致围产期小头畸形，而未成熟神经元中的缺失则不会。表明NMD在祖细胞中的关键作用。Upf2敲除（KO）延长放射状神经胶质祖细胞的细胞周期，促进它们向中间祖细胞的过渡，并导致上层神经元减少。CRISPRi筛选确定了Trp53敲低挽救Upf2KO祖细胞而没有全局逆转NMD抑制，暗示大多数NMD靶标对细胞周期缺陷的边际贡献。整合的功能基因组学表明，NMD降解选择性TRP53下游靶标，包括Cdkn1a,which,如果没有国家导弹防御系统的压制，减缓细胞周期。Trp53KO恢复祖细胞池并挽救Upf2KO小鼠的小头畸形。因此,NMD在发育中的大脑中的一个生理作用是降解选择性TRP53靶标以控制祖细胞周期和大脑大小。
