Translational derepression of Elavl4 isoforms at their alternative 5′ UTRs determines neuronal development

Abstract

Neurodevelopment requires precise regulation of gene expression, including posttranscriptional regulatory events such as alternative splicing and mRNA translation. However, translational regulation of specific isoforms during neurodevelopment and the mechanisms behind it remain unknown. Using RNA-seq analysis of mouse neocortical polysomes, here we report translationally repressed and derepressed mRNA isoforms during neocortical neurogenesis whose orthologs include risk genes for neurodevelopmental disorders. We demonstrate that the translation of distinct mRNA isoforms of the RNA binding protein (RBP), Elavl4, in radial glia progenitors and early neurons depends on its alternative 5′ UTRs. Furthermore, 5′ UTR-driven Elavl4 isoform-specific translation depends on upstream control by another RBP, Celf1. Celf1 regulation of Elavl4 translation dictates development of glutamatergic neurons. Our findings reveal a dynamic interplay between distinct RBPs and alternative 5′ UTRs in neuronal development and underscore the risk of post-transcriptional dysregulation in co-occurring neurodevelopmental disorders.

Developmental and behavioral phenotypes in a new mouse model of DDX3X syndrome

“…In parallel, post-transcriptional control is emerging as key for shaping cortical development (65, 69–73), and our findings and those by Lennox et al (2020) (3) add to this growing body of evidence. Lennox et al (2020) found that in utero knockdown of ~25% of Ddx3x in E14.5 cortices results in an increase in the proliferating pool and a decrease in post-mitotic neurons.…”

“…In addition to the sensory and motor phenotypes, Ddx3x +/mice show anxiety-like behaviors, hyperactivity, and specific deficits in the initial context-dependent recall of fear memory. Albeit complex and interlinked, the circuits subserving these behaviors require the cortex, the amygdala, and the hippocampus (34,35,59) In parallel, post-transcriptional control is emerging as key for shaping cortical development (65,(69)(70)(71)(72)(73), and our findings and those by Lennox et al (2020) (3) add to this growing body of evidence. Lennox et al (2020) found that in utero knockdown of ~25% of Ddx3x in E14.5 cortices results in an increase in the proliferating pool and a decrease in post-mitotic neurons.…”

“…Post-transcriptional control is surfacing as a significant source of risk for neurodevelopmental disorders. For example, risk genes for NDDs are enriched in targets of post-transcriptional regulators that are in turn encoded by risk genes, including RNA-binding proteins FMR1 (64), CELF4 (65) and RBFOX1 (64, 66, 67). Ddx3x regulates the translation of a subset of mRNAs in both neural progenitors (3) and post-mitotic neurons (3, 10) and amongst them is Rac1 , whose human orthologous gene is associated with ID (68).…”

Extrinsic Regulators of mRNA Translation in Developing Brain: Story of WNTs

“…The development of this complex laminar structure requires an intricate progression of spatially and temporally controlled molecular events starting from neural stem cells [ 2 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. The disruption of these events can lead to abnormal neocortical development associated with neurological and psychiatric disorders, such as epileptic encephalopathy (EE), autism spectrum disorder (ASD), and intellectual disability (ID), which are often expressed simultaneously [ 11 , 12 ]. The neocortical structure gives rise to six horizontal layers (I to VI), segregated principally by cell type and the specific site of neuronal connections.…”

“…HuR interacts with both common and unique subsets of mRNAs during early and late neurogenesis, suggesting that mRNA targets of RBPs evolve as a function of time [ 50 ]. Recent interesting work demonstrates that upstream RBP, Celf1, regulates the 5′ UTR-driven isoform-specific translation of another RBP, Elavl4, which results in the specific development of glutamatergic neurons [ 12 ]. These findings reveal a dynamic interplay between distinct RBPs and alternative 5′ UTRs in neuronal development.…”