Regulation of the Alternative Neural Transcriptome by ELAV/Hu RNA Binding Proteins

Abstract

The process of alternative polyadenylation (APA) generates multiple 3' UTR isoforms for a given locus, which can alter regulatory capacity and on occasion change coding potential. APA was initially characterized for a few genes, but in the past decade, has been found to be the rule for metazoan genes. While numerous differences in APA profiles have been catalogued across genetic conditions, perturbations, and diseases, our knowledge of APA mechanisms and biology is far from complete. In this review, we highlight recent findings regarding the role of the conserved ELAV/Hu family of RNA binding proteins (RBPs) in generating the broad landscape of lengthened 3' UTRs that is characteristic of neurons. We relate this to their established roles in alternative splicing, and summarize ongoing directions that will further elucidate the molecular strategies for neural APA, the in vivo functions of ELAV/Hu RBPs, and the phenotypic consequences of these regulatory paradigms in neurons.

1-L Transcription in Alzheimer’s Disease

“…ELAVL2 (ELAV-like RNA binding protein 2) is an ELAV1/HUR ( Figure 2 ) homolog and belongs to the neuronal-specific mammalian embryonic lethal, abnormal vision-like (ELAVL)2, 3 and 4 RBPs, which are an RBP family based on homology to ELAV protein in Drosophila and regulate the splicing pre-mRNAs [ 109 ] and the transport, stabilization, localization, and translation of mRNAs [ 110 ]. ELAVL2 interacts with hnRNP K to control neuronal differentiation, and regulates axonogenesis via post-transcriptional interaction with genes involved in neurodevelopment, transport, localization, and cytoskeleton, including GAP43 [ 110 ].…”

A critical developmental window for ELAV/Hu-dependent mRNA signatures at the onset of neuronal differentiation

“…In contrast to the majority of other key regulators that top the hierarchy of developmental programs—typically transcription factors—nuclear ELAV/Hu proteins exert their function in neurogenesis by mediating the production of neural mRNA isoforms not seen in other cell types. The recent characterization of ELAV-dependent signatures genome wide ( Carrasco et al., 2020 ; Lee et al., 2021 ) has brought to light the extent of ELAV’s influence on the coding and non-coding neuronal transcriptome and raised the question of how alternative exons and 3′ UTRs impact neurogenesis and neuron physiology ( Wei and Lai, 2022 ).…”

“…The synthesis of neuronal RNA signatures depends on ELAV/Hu proteins (reviewed in Hilgers, 2022 ; Wei and Lai, 2022 ). The members of this highly conserved family of RNA-binding proteins (RBPs) constitute widely used markers for neuronal identity: in most animals studied to date, at least one ELAV/Hu protein is expressed in all post-mitotic neurons from inception and throughout development ( Campos et al., 1985 , 1987 ; Pascale et al., 2008 ; Robinow and White, 1988 ; Yao et al., 1993 ).…”

“…ELAV/Hu proteins bind to U-rich regions in thousands of RNAs ( Carrasco et al., 2020 ; Scheckel et al., 2016 ) and regulate diverse aspects of RNA metabolism, from co-transcriptional processing to mRNA stability and translation ( Ince-Dunn et al., 2012 ; Mukherjee et al., 2011 ; Pascale et al., 2005 ; Tebaldi et al., 2018 ; Tiruchinapalli et al., 2008 ; Yokoi et al., 2017 ). At the co-transcriptional level, the role of ELAV/Hu proteins in the production of neuron-specific AS and APA has been demonstrated in flies ( Carrasco et al., 2020 ; Hilgers et al., 2012 ; Koushika et al., 1996 ; Lisbin et al., 2001 ; Soller and White, 2003 ; Wei and Lai, 2022 ; Wei et al., 2020 ) and mammals ( Grassi et al., 2018 ; Mansfield and Keene, 2012 ; Scheckel et al., 2016 ; Zhu et al., 2006 ). In Drosophila , the three ELAV/Hu paralogs appear consecutively in the course of development: found in neurons (FNE) expression follows ELAV’s during embryogenesis ( Samson and Chalvet, 2003 ), whereas RBP9 is not detectable before larval stages ( Kim and Baker, 1993 ).…”

Combining affinity purification and mass spectrometry to define the network of the nuclear proteins interacting with the N-terminal region of FMRP

“…In this line of view, FMRP may act as a hub protein that could follow, partially or completely, the fate of its target mRNAs. Interestingly, some studies indicate that other neuronal mRNA-binding protein such as ELAV or SMN proteins, involved in mRNA dendritic transport in neurons, transit through the nucleus and participate in early post-transcriptional regulatory events such as pre-mRNA splicing or poly-adenylation ( Colombrita et al, 2013 ; Raimer et al, 2017 ; Ravanidis et al, 2018 ; Jung and Lee 2021 ; Wei and Lai 2022 ). We propose here that the workflow we set up, combining an efficient nuclear fractionation from rat forebrain coupled to affinity pull down followed by identification using tandem mass spectrometry, could be adapted to assess the nuclear interactome of these dual-distributed but predominantly cytoplasmic neuronal factors.…”