Epistatic interactions between NMD and TRP53 control progenitor cell maintenance and brain size
Lin Lin1, Jingrong Zhao1, Naoto Kubota1
1Division 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.
Neuron
|May 2, 2024
Summary
Nonsense-mediated mRNA decay (NMD) is crucial for brain development. In mice, NMD factor Upf2 deletion causes microcephaly by altering progenitor cell cycles, a defect rescued by targeting Trp53.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Mutations in nonsense-mediated mRNA decay (NMD) factors are linked to neurodevelopmental disorders.
- NMD plays a critical role in regulating gene expression during development.
Purpose of the Study:
- To investigate the role of NMD in mouse neural progenitor cells during brain development.
- To identify specific NMD targets and pathways involved in neurodevelopmental defects.
Main Methods:
- Utilized Upf2 knockout (KO) mouse models to study NMD function in neural progenitor cells.
- Employed CRISPR interference (CRISPRi) screening to identify genetic modifiers of NMD deficiency.
- Integrated functional genomics and cell cycle analysis.
Main Results:
- Deletion of Upf2 in mouse embryonic neural progenitor cells, but not immature neurons, caused perinatal microcephaly.
- Upf2 KO prolonged radial glia progenitor cell cycle and reduced upper-layer neuron production.
- Trp53 knockdown rescued Upf2KO progenitor defects, identifying CDKN1A as a key NMD target regulated by Trp53.
Conclusions:
- NMD regulates progenitor cell cycle and brain size by degrading selective Trp53 targets, such as Cdkn1a.
- Trp53 acts as a critical regulator in the NMD pathway's impact on brain development.
- This study elucidates a novel mechanism by which NMD controls brain size during development.
