p53-mediated neurodegeneration in the absence of the nuclear protein Akirin2

Purpose: We investigated the molecular function of the nuclear protein, Akirin2 (Aki2), in postmitotic excitatory cortical neurons and neural progenitor cells of the embryonic dorsal telencephalon. Method: We performed total RNA-Sequencing on the cortex of P35 CaMK-Cre;Aki2fl/fl mice and age matched controls. We compared this transcriptomic database to one obtained through total RNA-Sequencing of E10.5 Emx1-Cre;Aki2fl/fl dorsal telencephalon and age-matched controls . Results: We discovered slow degeneration through necroptosis in the Aki2 postmitotic forebrain mutants and dysregulation of many p53 target genes in both transcriptomics datasets. Reduction of the p53 gene in the CaMK-Cre;Aki2fl/fl line delays cell death; while knockout prevents it entirely. Conclusion: This study provides insight into the molecular mechanisms of Aki2 function in cortical neurons and identifies p53 as a molecular mediator of neuronal death in the absence of Aki2. Futhermore, it identifies several candidate Aki2-dependent genes dysregulated in both transcroptomic datasets and many candidate Aki2 target genes that are context dependent. cortical mRNA profiles of three P35 CaMK-Cre;Ak2fl/fl and four littermate control mice; dorsal telencephalon mRNA profile of four E10.5 Emx1-Cre;Aki2fl/fl and four littermate controls

研究目的：本研究旨在探究核蛋白Akirin2（简称Aki2）在胚胎背侧端脑的有丝分裂后兴奋性皮层神经元与神经祖细胞中的分子功能。
研究方法：本研究对P35龄CaMK-Cre;Aki2fl/fl小鼠及其同年龄段对照小鼠的皮层组织开展全转录组RNA测序（total RNA-Sequencing），并将所得转录组数据库与通过对E10.5龄Emx1-Cre;Aki2fl/fl背侧端脑组织进行全转录组RNA测序所获得的数据库进行对比分析。
研究结果：本研究发现，在Aki2缺失的有丝分裂后前脑突变体中，细胞通过坏死性凋亡发生缓慢退行性变；且在两组转录组数据中，均存在大量p53靶基因的表达失调现象。在CaMK-Cre;Aki2fl/fl模型中敲低p53基因可延缓细胞死亡进程，而完全敲除p53则可完全阻断该死亡过程。
研究结论：本研究阐明了Aki2在皮层神经元中发挥功能的分子机制，并确认p53是Aki2缺失状态下神经元死亡的分子介导因子。此外，本研究还在两组转录组数据中筛选出多个受Aki2调控的失调候选基因，以及一批具有上下文依赖性的Aki2潜在靶基因。本数据集包含3只P35龄CaMK-Cre;Aki2fl/fl小鼠与4只同窝对照小鼠的皮层mRNA表达谱，以及4只E10.5龄Emx1-Cre;Aki2fl/fl小鼠与4只同窝对照小鼠的背侧端脑mRNA表达谱。