DNA replication fork speed acts as a pacer in cortical neurogenesis

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.