1. Developmental Attenuation of Neuronal Apoptosis by Neural-Specific Splicing of Bak1 Microexon.
- Author
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Lin, Lin, Zhang, Min, Stoilov, Peter, Chen, Liang, and Zheng, Sika
- Subjects
AS-NMD ,BAK ,BCL2 family proteins ,NMD ,PTB ,PTBP ,PTBP2 ,UPF2 ,alternative splicing ,cell death ,neural development ,neurogenesis ,neuronal lifespan ,Animals ,Apoptosis ,Brain ,Cell Line ,Tumor ,Cells ,Cultured ,Female ,Heterogeneous-Nuclear Ribonucleoproteins ,Male ,Mice ,Mice ,Inbred C57BL ,Mutation ,Neural Stem Cells ,Neurogenesis ,Nonsense Mediated mRNA Decay ,Polypyrimidine Tract-Binding Protein ,RNA Splicing ,bcl-2 Homologous Antagonist-Killer Protein - Abstract
Continuous neuronal survival is vital for mammals because mammalian brains have limited regeneration capability. After neurogenesis, suppression of apoptosis is needed to ensure a neurons long-term survival. Here we describe a robust genetic program that intrinsically attenuates apoptosis competence in neurons. Developmental downregulation of the splicing regulator PTBP1 in immature neurons allows neural-specific splicing of the evolutionarily conserved Bak1 microexon 5. Exon 5 inclusion triggers nonsense-mediated mRNA decay (NMD) and unproductive translation of Bak1 transcripts (N-Bak mRNA), leading to suppression of pro-apoptotic BAK1 proteins and allowing neurons to reduce apoptosis. Germline heterozygous ablation of exon 5 increases BAK1 proteins exclusively in the brain, inflates neuronal apoptosis, and leads to early postnatal mortality. Therefore, neural-specific exon 5 splicing and depletion of BAK1 proteins uniquely repress neuronal apoptosis. Although apoptosis is important for development, attenuation of apoptosis competence through neural-specific splicing of the Bak1 microexon is essential for neuronal and animal survival.
- Published
- 2020