Mutations in centrosome genes deplete neural progenitor cells (NPCs) during brain development, causing microcephaly. While NPC attrition is linked to TP53‐mediated cell death in several microcephaly models, how TP53 is activated remains unclear. In cultured cells, mitotic delays resulting from centrosome loss prevent the growth of unfit daughter cells by activating a pathway involving 53BP1, USP28, and TP53, termed the mitotic surveillance pathway. Whether this pathway is active in the developing brain is unknown. Here, we show that the depletion of centrosome proteins in NPCs prolongs mitosis and increases TP53‐mediated apoptosis. Cell death after a delayed mitosis was rescued by inactivation of the mitotic surveillance pathway. Moreover, 53BP1 or USP28 deletion restored NPC proliferation and brain size without correcting the upstream centrosome defects or extended mitosis. By contrast, microcephaly caused by the loss of the non‐centrosomal protein SMC5 is also TP53‐dependent but is not rescued by loss of 53BP1 or USP28. Thus, we propose that mutations in centrosome genes cause microcephaly by delaying mitosis and pathologically activating the mitotic surveillance pathway in the developing brain.

中文翻译：

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中心体缺陷通过激活 53BP1-USP28-TP53 有丝分裂监视途径导致小头畸形


中心体基因突变会在大脑发育过程中耗尽神经祖细胞（NPC），导致小头畸形。虽然在一些小头畸形模型中 NPC 损耗与 TP53 介导的细胞死亡有关，但 TP53 是如何激活的仍不清楚。在培养细胞中，中心体丢失导致的有丝分裂延迟通过激活涉及 53BP1、USP28 和 TP53 的途径（称为有丝分裂监视途径）来阻止不健康子细胞的生长。该通路在发育中的大脑中是否活跃尚不清楚。在这里，我们发现 NPC 中中心体蛋白的消耗会延长有丝分裂并增加 TP53 介导的细胞凋亡。有丝分裂延迟后的细胞死亡可以通过有丝分裂监视途径的失活来挽救。此外，53BP1或USP28缺失恢复了NPC增殖和大脑大小，但没有纠正上游中心体缺陷或延长有丝分裂。相比之下，由非中心体蛋白 SMC5 缺失引起的小头畸形也是 TP53 依赖性的，但不能通过 53BP1 或 USP28 的缺失来挽救。因此，我们提出中心体基因突变通过延迟有丝分裂和病理性激活发育中大脑的有丝分裂监视途径而导致小头畸形。