Genome integrity and neurogenesis of postnatal hippocampal neural stem/progenitor cells require a unique regulator Filia

Sci Adv. 2020 Oct 28;6(44):eaba0682. doi: 10.1126/sciadv.aba0682.

Jingzheng Li ¹ ² ³, Yafang Shang ³ ⁴, Lin Wang ¹ ², Bo Zhao ¹ ², Chunli Sun ¹ ² ³, Jiali Li ⁵, Siling Liu ⁵, Cong Li ¹ ² ³, Min Tang ¹ ² ³, Fei-Long Meng ⁶, Ping Zheng ⁷ ² ⁸ ⁹

Affiliations

1 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
2 Yunnan Key Laboratory of Animal Reproduction, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
3 University of Chinese Academy of Sciences, Beijing 101408, China.
4 State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
5 Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650201, China.
6 State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China. [email protected] [email protected].
7 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China. [email protected] [email protected].
8 KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
9 Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650201, China.

PMID: 33115731 DOI: 10.1126/sciadv.aba0682

Abstract

Endogenous DNA double-strand breaks (DSBs) formation and repair in neural stem/progenitor cells (NSPCs) play fundamental roles in neurogenesis and neurodevelopmental disorders. NSPCs exhibit heterogeneity in terms of lineage fates and neurogenesis activity. Whether NSPCs also have heterogeneous regulations on DSB formation and repair to accommodate region-specific neurogenesis has not been explored. Here, we identified a regional regulator Filia, which is predominantly expressed in mouse hippocampal NSPCs after birth and regulates DNA DSB formation and repair. On one hand, Filia protects stalling replication forks and prevents the replication stress-associated DNA DSB formation. On the Other hand, Filia facilitates the homologous recombination-mediated DNA DSB repair. Consequently, Filia^-/- mice had impaired hippocampal NSPC proliferation and neurogenesis and were deficient in learning, memory, and mood regulations. Thus, our study provided the first proof of concept demonstrating the region-specific regulations of DSB formation and repair in subtypes of NSPCs.

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