Max-Planck-Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Faculty of Biology, Albert Ludwig University, 79104 Freiburg, Germany; International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB), 79108 Freiburg, Germany.
Max-Planck-Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
Cell Rep. 2022 Oct 25;41(4):111542. doi: 10.1016/j.celrep.2022.111542.
Cell-type-specific gene regulatory programs are essential for cell differentiation and function. In animal neurons, the highly conserved ELAV/Hu family of proteins promotes alternative splicing and polyadenylation of mRNA precursors to create unique neuronal transcript isoforms. Here, we assess transcriptome profiles and neurogenesis success in Drosophila models engineered to express differing levels of ELAV activity in the course of development. We show that the ELAV-mediated establishment of a subset of neuronal mRNA isoforms at the onset of neuron differentiation constitutes a developmental bottleneck that cannot be overcome later by the nuclear activation of the paralog found in neurons (FNE). Loss of ELAV function outside of that critical time window results in neurological defects. We find that FNE, when activated early enough, can restore ELAV-dependent neuronal mRNA isoforms and fully rescue development. Our findings demonstrate the essential role of robust cellular strategies to maintain ELAV activity and intact neuronal signatures in neurogenesis and neuronal function.
细胞类型特异性基因调控程序对于细胞分化和功能至关重要。在动物神经元中，高度保守的 ELAV/Hu 家族蛋白促进 mRNA 前体的可变剪接和多聚腺苷酸化，以产生独特的神经元转录本异构体。在这里，我们评估了在果蝇模型中表达不同 ELAV 活性水平的转录组谱和神经发生成功情况。我们表明，ELAV 在神经元分化开始时介导的一组神经元 mRNA 异构体的建立构成了一个发育瓶颈，在这个瓶颈之后，神经元中发现的同源物（FNE）的核激活无法克服。ELAV 功能的丧失发生在这个关键时间窗口之外，会导致神经缺陷。我们发现，FNE 如果在足够早的时候被激活，就可以恢复依赖 ELAV 的神经元 mRNA 异构体，并完全挽救发育。我们的研究结果表明，在神经发生和神经元功能中，维持 ELAV 活性和完整的神经元特征的强大细胞策略具有至关重要的作用。
Zotero 插件
