Early establishment of neuronal transcriptome signatures is critical for nervous system differentiation

Cell-type-specific gene regulatory programs are crucial for cell differentiation and function. In animal neurons, the highly conserved ELAV/Hu family of proteins promotes alternative splicing and alternative polyadenylation of mRNA precursors to create unique neuronal transcript isoforms. Here, we show in Drosophila that the ELAV-mediated establishment of neuron-specific mRNA isoforms at the onset of neuronal differentiation constitutes a developmental bottleneck. While ELAV loss during a critical developmental time window is lethal and cannot be rescued later by the activation of the ELAV-like paralogue FNE, loss of ELAV function outside of that window results in neurological defects of differing nature and degree. FNE can effectively perform all molecular functions of ELAV, and, when activated early enough, fully rescue neuronal development. Our findings demonstrate the essential role of robust ELAV activity and intact neuronal signatures in the differentiation and function of the nervous system. Overall design: mRNA-seq in Drosophila embyros and adults in different genotypes and stages of development. Three (adults) or four (embryos) replicates containing each 12-15 individuals were sequenced.