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Updated: Aug 23, 2026
Assessing Cell Cycle Progression of Neural Stem and Progenitor Cells in the Mouse Developing Brain after Genotoxic Stress
Published on: May 7, 2014
MCM3 Safeguards Neural Progenitor Maintenance and Cortical Development Against Replication-Associated Stress
Zhenyan Xu1,2, Jing Chen1, Sheng He1
1Tongling People's Hospital, Tongling, 244000, China.
Abstract:
Faithful genome duplication during neurogenesis relies on the licensing of surplus replication origins, and hypomorphic variants in MCM3 have been associated with microcephaly and related growth disorders. Using in utero electroporation in embryonic mouse cortex, we show that acute partial depletion of MCM3 disrupts cortical progenitor development. MCM3 knockdown reduced EdU incorporation and PCNA positivity among GFP-positive cells in the VZ, indicating decreased S-phase engagement or impaired cell-cycle progression. It also increased replication-stress-associated signals, including γ-H2AX and p-RPA2(T21), but did not induce detectable cleaved caspase-3 activation. These changes were accompanied by a reduction in the population of electroporated neural progenitors, leading to decreased neuronal output. In addition, MCM3-depleted neuronal progeny showed altered radial distribution and reduced callosal axon extension. Together, these findings support a role for MCM3 in maintaining progenitor proliferative capacity and genome-stress tolerance during cortical development, and provide mechanistic insight into how partial MCM3 deficiency may contribute to microcephaly-related neurodevelopmental disorders.
Insights
MCM3 deficiency impairs neural progenitor cells during brain development, impacting cell cycle progression and leading to reduced neuronal output. This offers insights into microcephaly and neurodevelopmental disorders.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Faithful genome duplication during neurogenesis requires replication origin licensing.
- Hypomorphic variants in MCM3 are linked to microcephaly and growth disorders.
Purpose of the Study:
- To investigate the role of MCM3 in cortical progenitor development and neurogenesis.
- To understand the mechanistic basis of microcephaly-related disorders linked to MCM3 deficiency.
Main Methods:
- Utilized in utero electroporation in embryonic mouse cortex to acutely deplete MCM3 in neural progenitors.
- Assessed cell-cycle progression using EdU and PCNA markers.
- Quantified replication stress markers (γ-H2AX, p-RPA2(T21)) and apoptosis (cleaved caspase-3).
- Evaluated progenitor population size, neuronal output, and neuronal migration/axon extension.
Main Results:
- Partial MCM3 depletion reduced S-phase engagement and impaired cell-cycle progression in cortical progenitors.
- MCM3 knockdown increased replication stress but did not induce apoptosis.
- Reduced neural progenitor numbers and neuronal output were observed.
- MCM3-depleted neurons exhibited altered radial distribution and reduced callosal axon extension.
Conclusions:
- MCM3 is crucial for maintaining progenitor proliferative capacity and genome-stress tolerance during cortical development.
- Partial MCM3 deficiency disrupts neurogenesis, providing mechanistic insights into microcephaly-related neurodevelopmental disorders.
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