1. Developmental Attenuation of Neuronal Apoptosis by Neural-Specific Splicing of Bak1 Microexon.
- Author
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Lin L, Zhang M, Stoilov P, Chen L, and Zheng S
- Subjects
- Animals, Brain growth & development, Brain metabolism, Cell Line, Tumor, Cells, Cultured, Female, Heterogeneous-Nuclear Ribonucleoproteins genetics, Heterogeneous-Nuclear Ribonucleoproteins metabolism, Male, Mice, Mice, Inbred C57BL, Mutation, Neural Stem Cells cytology, Neural Stem Cells metabolism, Nonsense Mediated mRNA Decay, Polypyrimidine Tract-Binding Protein genetics, Polypyrimidine Tract-Binding Protein metabolism, bcl-2 Homologous Antagonist-Killer Protein metabolism, Apoptosis, Neurogenesis, RNA Splicing, bcl-2 Homologous Antagonist-Killer Protein genetics
- 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 neuron's 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., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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