The molecular genetics of nELAVL in brain development and disease

Abstract

Embryonic development requires tight control of gene expression levels, activity, and localisation. This control is coordinated by multiple levels of regulation on DNA, RNA and protein. RNA-binding proteins (RBPs) are recognised as key regulators of post-transcriptional gene regulation, where their binding controls splicing, polyadenylation, nuclear export, mRNA stability, translation rate and decay. In brain development, the ELAVL family of RNA binding proteins undertake essential functions across spatiotemporal windows to help regulate and specify transcriptomic programmes for cell specialisation. Despite their recognised importance in neural tissues, their molecular roles and connections to pathology are less explored. Here we provide an overview of the neuronal ELAVL family, noting commonalities and differences amongst different species, their molecular characteristics, and roles in the cell. We bring together the available molecular genetics evidence to link different ELAVL proteins to phenotypes and disease, in both the brain and beyond, including ELAVL2, which is the least studied ELAVL family member. We find that ELAVL-related pathology shares a common neurological theme, but different ELAVL proteins are more strongly connected to different phenotypes, reflecting their specialised expression across time and space.

A Single-Cell Landscape of Spermioteleosis in Mice and Pigs

“…This could indicate that the spermatogonia of mice are primarily type A intermediate spermatogonia, while those of pigs are predominantly type B spermatogonia [68]. In pig spermatogonia, the expression of ELAVL2, a little-studied ELAVL family member [69], is particularly active. Interestingly, the significantly differentially expressed genes identified in the pseudotime analysis of pig spermatogonia indicated that ELAVL2 was highly expressed in pig spermatogonia.…”

ELAV mediates circular RNA biogenesis in neurons

“…The accumulation of circRNAs in the brain is a molecular landmark across animals 1,12,13 . Considering the similarity, in terms of sequence and expression patterns, of neuronal ELAV-like (nELAV) proteins from flies to humans 29,57,58 , conserved mechanisms may be at play to regulate intron pairing and neuronal circRNA biogenesis. Moreover, the predominantly cytoplasmically localized human nELAV protein HuD binds to a quarter of all brain-expressed circRNAs as well as many host transcripts 59 ; in context with our findings, this raises the hypothesis that in evolutionarily distant species, nuclear nELAV proteins (such as ELAV) mediate circRNA biogenesis, and that binding of mature circRNAs by cytoplasmic nELAVs (such as HuD) regulates their local expression and function.…”

Translational study on the role of genetic and prenatal risk factors in neurodevelopmental psychiatric disorders

“…These were implicated in HPC LTP of the slow inhibitory postsynaptic currents -an inhibitionrelated LTP that Nova2 knockout mice lack, suggesting specific long-term changes of synaptic plasticity (Huang et al, 2005). Interestingly, NOVA and RBFOX might work as splicing regulators in a synergistic manner by binding the same mRNA, skipping exons when bound upstream or on target, or including the exon when bound downstream (Raj & Blencowe, 2015;Zhang et al, 2010); see also Figures 8C, Figure and stress response (Clayton et al, 1998;Keene, 1999;Mulligan & Bicknell, 2023). ELAVL2 has not been widely studied in rodents due to high mortality rate at weaning following growth…”

“…impairments, but has been implicated in memory formation in other vertebrate models (Mulligan & Bicknell, 2023). ELAVL3 upregulation during development promotes cell fate of progenitors of GABAergic inhibitory neurons (see Figure 1.10C), and loss in murine neural stem cells delays neuronal differentiation (Grassi et al, 2018).…”

“…RBPs of the nELAVL family exert pleiotropic effects on a multitude of degenerative and psychomotor disorders (Alzheimer's (AD) and Parkinson's (PD) disease, amyotrophic lateral sclerosis, tremor, ataxia), embryogenetic deficits, as well as ASD, SCZ, and related cognitive traits (Mulligan & Bicknell, 2023). These proteins are also relevant in SUDs (Bryant & Yazdani, 2016) and in OCD through upregulation of multiple postsynaptic targets (van de Vondervoort et al, 2016).…”