Regulation of neuronal RNA signatures by ELAV/Hu proteins

The RNA‐binding proteins encoded by the highly conserved elav/Hu gene family, found in all metazoans, regulate the expression of a wide range of genes, at both the co‐transcriptional and posttranscriptional level. Nervous‐system‐specific ELAV/Hu proteins are prominent for their essential role in neuron differentiation, and mutations have been associated with human neurodevelopmental and neurodegenerative diseases. Drosophila ELAV, the founding member of the protein family, mediates the synthesis of neuronal RNA signatures by promoting alternative splicing and alternative polyadenylation of hundreds of genes. The recent identification of ELAV's direct RNA targets revealed the protein's central role in shaping the neuronal transcriptome, and highlighted the importance of neuronal transcript signatures for neuron maintenance and organism survival. Animals have evolved multiple cellular mechanisms to ensure robustness of ELAV/Hu function. In Drosophila, elav autoregulates in a 3′UTR‐dependent manner to maintain optimal protein levels. A complete absence of ELAV causes the activation and nuclear localization of the normally cytoplasmic paralogue FNE, in a process termed EXon‐Activated functional Rescue (EXAR). Other species, including mammals, seem to utilize different strategies, such as protein redundancy, to maintain ELAV protein function and effectively safeguard the identity of the neuronal transcriptome. This article is categorized under: RNA Processing > 3′ End Processing RNA in Disease and Development > RNA in Development RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications Functions of ELAV/Hu family proteins in animal neurons. In the nucleus, ELAV/Hu proteins mediate alternative splicing and alternative polyadenylation co‐transcriptionally. In the cytoplasm, ELAV/Hu proteins bind mRNAs to regulate posttranscriptional processes. While the universal mRNA isoform is expressed in many cell types (including neurons), the neuronal mRNA isoform is restricted to the nervous system.