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.

持续的神经元存活对哺乳动物至关重要，因为哺乳动物大脑的再生能力有限。神经发生后，需要抑制细胞凋亡以确保神经元的长期存活。在这里，我们描述了一个强大的遗传程序，它本质上减弱了神经元的凋亡能力。未成熟神经元中剪接调节因子 PTBP1 的发育下调允许进化上保守的Bak1微外显子 5 的神经特异性剪接。外显子 5 包含触发无义介导的 mRNA 衰减 (NMD) 和Bak1 的非生产性翻译转录本（N-Bak mRNA），从而抑制促凋亡 BAK1 蛋白并允许神经元减少细胞凋亡。外显子 5 的种系杂合子消融仅增加大脑中的 BAK1 蛋白，加剧神经元凋亡，并导致出生后早期死亡。因此，神经特异性外显子 5 剪接和 BAK1 蛋白的消耗独特地抑制了神经元凋亡。尽管细胞凋亡对发育很重要，但通过Bak1微外显子的神经特异性剪接来减弱细胞凋亡能力对于神经元和动物的生存至关重要。