Epistatic interactions between NMD and TRP53 control progenitor cell maintenance and brain size

Lin Lin; Jingrong Zhao; Naoto Kubota; Zhelin Li; Yi-Li Lam; Lauren P Nguyen; Lu Yang; Sheela P Pokharel; Steven M Blue; Brian A Yee; Renee Chen; Gene W Yeo; Chun-Wei Chen; Liang Chen; Sika Zheng

doi:10.1016/j.neuron.2024.04.006

Epistatic interactions between NMD and TRP53 control progenitor cell maintenance and brain size

Neuron. 2024 Apr 22:S0896-6273(24)00244-7. doi: 10.1016/j.neuron.2024.04.006. Online ahead of print.

Authors

Lin Lin¹, Jingrong Zhao¹, Naoto Kubota¹, Zhelin Li², Yi-Li Lam¹, Lauren P Nguyen³, Lu Yang⁴, Sheela P Pokharel⁴, Steven M Blue⁵, Brian A Yee⁵, Renee Chen⁴, Gene W Yeo⁵, Chun-Wei Chen⁶, Liang Chen⁷, Sika Zheng⁸

Affiliations

¹ Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA 92521, USA; Center for RNA Biology and Medicine, University of California, Riverside, Riverside, CA 92521, USA.
² Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA 92521, USA.
³ Interdepartmental Neuroscience Program, University of California, Riverside, Riverside, CA 92521, USA.
⁴ Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
⁵ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, USA.
⁶ Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA; City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
⁷ Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA.
⁸ Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA 92521, USA; Center for RNA Biology and Medicine, University of California, Riverside, Riverside, CA 92521, USA; Interdepartmental Neuroscience Program, University of California, Riverside, Riverside, CA 92521, USA. Electronic address: sikaz@ucr.edu.

PMID: 38697111
DOI: 10.1016/j.neuron.2024.04.006

Abstract

Mutations in human nonsense-mediated mRNA decay (NMD) factors are enriched in neurodevelopmental disorders. We show that deletion of key NMD factor Upf2 in mouse embryonic neural progenitor cells causes perinatal microcephaly but deletion in immature neurons does not, indicating NMD's critical roles in progenitors. Upf2 knockout (KO) prolongs the cell cycle of radial glia progenitor cells, promotes their transition into intermediate progenitors, and leads to reduced upper-layer neurons. CRISPRi screening identified Trp53 knockdown rescuing Upf2KO progenitors without globally reversing NMD inhibition, implying marginal contributions of most NMD targets to the cell cycle defect. Integrated functional genomics shows that NMD degrades selective TRP53 downstream targets, including Cdkn1a, which, without NMD suppression, slow the cell cycle. Trp53KO restores the progenitor cell pool and rescues the microcephaly of Upf2KO mice. Therefore, one physiological role of NMD in the developing brain is to degrade selective TRP53 targets to control progenitor cell cycle and brain size.

Keywords: EJC; PAX6; TBR2; Upf1; Upf3a; Upf3b; cell division; neurogenesis; p21; p53; progenitor cell competence.

Abstract

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