Regulation of neuronal RNA signatures by ELAV/Hu proteins

Abstract

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. Nervoussystem-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 0 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.

miR-26 deficiency causes alterations in lens transcriptome and results in adult-onset cataract

“…Nevertheless, both the lens fiber cells and neurons share several molecular and structural features not commonly found in other tissues, including the expression of nestin, synaptic proteins, glutamate receptors, and GABA receptors [43][44][45][46][47] . Some of these neural characteristics may be driven by molecular regulators of alternative splicing that are shared in both lens and neurons, including several members of the ELAV/Hu proteins 48,49 . Despite this, several recent studies have suggested that the suppression of neural gene expression in lens cells may be an important component of normal lens development and function 50,51 .…”

miR-26 Deficiency Causes Alterations in Lens Transcriptome and Results in Adult-Onset Cataract

“… 51 – 55 Some of these neural characteristics may be driven by molecular regulators of alternative splicing that are shared in both lens and neurons, including several members of the ELAV/Hu proteins. 56 , 57 Despite this, several recent studies have suggested that the suppression of neural gene expression in lens cells may be an important component of normal lens development and function. 58 , 59…”

Sex and the basal mRNA synthesis machinery

“…However, mice lacking the Cstf2t gene showed clear sex‐specific differences in behavior and memory (Harris et al, 2016). Alternate splicing and polyadenylation contribute to a multitude of unique neuronal gene expression patterns (Fisher & Feng, 2022; Hilgers, 2022; Landinez‐Macias & Urwyler, 2021). The Cstf2t report highlights the importance of understanding all mechanisms by which sex may impact RNA processing.…”

“…None of the genes encoding the 120 selected proteins were imprinted. However, the brain, with its fascinatingly complex RNA biology, is rich in genes whose expression is restricted to one allele (Fisher & Feng, 2022; Hilgers, 2022; Landinez‐Macias & Urwyler, 2021; Tucci et al, 2019). For example, the classic reciprocally imprinted Prader‐Willi and Angelman neurodevelopmental syndromes involve deletion of an overlapping region.…”