DNA replication fork speed acts as a pacer in cortical neurogenesis

Jianhong Wang, Yifan Kong, Xuezhuang Li, Dexi Chen, Kun Xiang, Yulian Tan and Lei Shi ()
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Jianhong Wang: Chinese Academy of Sciences, State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology
Yifan Kong: Chinese Academy of Sciences, State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology
Xuezhuang Li: Chinese Academy of Sciences, State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology
Dexi Chen: Chinese Academy of Sciences, State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology
Kun Xiang: The First People’s Hospital of Yunnan Province
Yulian Tan: Chinese Academy of Sciences, State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology
Lei Shi: Chinese Academy of Sciences, State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract DNA replication fork speed, which controls the rate of genome duplication, has emerged as a key regulator of cellular plasticity. However, its role in neurogenesis remains unexplored. Mini-chromosome maintenance complex (MCMs)-binding protein (MCMBP) functions as a chaperone for newly synthesized MCMs, increasing chromatin coverage to restrain fork speed. We demonstrate that selectively deleting Mcmbp in neural progenitor radial glial cells (RGCs) accelerates fork speed, triggering DNA damage, micronuclei formation, and widespread apoptosis, which ultimately activates p53 and causes microcephaly. Unexpectedly, concurrent deletion of Trp53 and Mcmbp further increases fork speed, leading to extensive RGC detachment from the ventricular zone and acquisition of outer-RGC characteristics. Mechanistically, we find that the MCM complex coordinates DNA and centrosome duplication, thereby mediating RGC attachment. Behavioral analysis reveals that embryonic replication stress induced by accelerated fork speed results in lasting anxiety-like behavior in adult mice. These findings unveil a role for replication fork speed in neurogenesis.

Date: 2025
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DOI: 10.1038/s41467-025-65269-y

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