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Temporally defined neocortical translation and polysome assembly is determined by the RNA-binding protein, Hu antigen R

ABSTRACT: Precise spatiotemporal control of mRNA translation machinery is essential to proper development of highly complex systems like the neocortex. Here, we show that an RNA-binding protein, Hu antigen R (HuR), regulates both neocorticogenesis and specificity of neocortical translation machinery in a developmental stage-dependent manner in mice. Neocortical absence of HuR alters the phosphorylation states of the initiation and elongation factors of the core translation machinery. In addition, HuR regulates the temporally specific positioning of functionally related mRNAs into the active translation sites, the polysomes. HuR also determines the specificity of neocortical polysomes by defining their combinatorial composition of ribosomal proteins and initiation and elongation factors. For some of the HuR-dependent proteins, the association with polysomes depends on the eIF2 alpha kinase 4 (eIF2ak4), which associated with HuR in prenatal developing neocortices. Finally, we found that deletion of HuR prior to embryonic day 10 (E10) disrupts both neocortical lamination and formation of the main neocortical commissure, the corpus callosum. Our study identifies a crucial role for HuR in neocortical development as a translational gatekeeper for functionally related mRNA subgroups and polysomal protein specificity.

ORGANISM(S): Mus musculus

PROVIDER: GSE50809 | GEO | 2014/08/25

SECONDARY ACCESSION(S): PRJNA219065

REPOSITORIES: GEO

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Temporally defined neocortical translation and polysome assembly is determined by the RNA-binding protein, Hu antigen R

Project description:Precise spatiotemporal control of mRNA translation machinery is essential to proper development of highly complex systems like the neocortex. Here, we show that an RNA-binding protein, Hu antigen R (HuR), regulates both neocorticogenesis and specificity of neocortical translation machinery in a developmental stagedependent manner in mice. Neocortical absence of HuR alters the phosphorylation states of the initiation and elongation factors of the core translation machinery. In addition, HuR regulates the temporally specific positioning of functionally related mRNAs into the active translation sites, the polysomes. HuR also determines the specificity of neocortical polysomes by defining their combinatorial composition of ribosomal proteins and initiation and elongation factors. For some of the HuR-dependent proteins, the association with polysomes depends on the eIF2 alpha kinase 4 (eIF2ak4), which associated with HuR in prenatal developing neocortices. Finally, we found that deletion of HuR prior to embryonic day 10 (E10) disrupts both neocortical lamination and formation of the main neocortical commissure, the corpus callosum. Our study identifies a crucial role for HuR in neocortical development as a translational gatekeeper for functionally related mRNA subgroups and polysomal protein specificity. Cortex was dissected from mouse pups at embryonic day 13 (E13) or the day of birth (P0).

2014-08-25 | E-GEOD-50809 | biostudies-arrayexpress

Microarray analysis of developing mouse cortex reveals regulation of ribosomal protein mRNAs throughout development

Project description:Neocortical development is spatiotemporally regulated by exogenous factors, but the mechanism regulating timed specificity of neocortical mRNA translation is unknown. We find that active mRNA translation sites (polysomes) contain ribosomal protein subsets that undergo dynamic spatiotemporal rearrangements during mouse neocortical development. Two samples of cortext total RNA each from four embryonic time points were collected.

2015-06-26 | E-GEOD-61751 | biostudies-arrayexpress

Microarray analysis of developing mouse cortex reveals regulation of ribosomal protein mRNAs throughout development

2015-06-26 | GSE61751 | GEO

RNA-binding proteins Cugbp1 and HuD regulate neocortical projection neuron identities under the translational control of Neurotrophin-3

Project description:Intrinsic molecular pathways in the central nervous system dictate neuronal cell fate during development. However, interplay of RNA binding proteins (RBPs) dictating mRNA translation, and their spatiotemporal extracellular regulators in neocortical neural stem cells during neurogenesis are poorly understood. Using an unbiased RNAseq screen of polysomes between early and mid-neurogenesis, we identified functionally related mRNA groups and their isoforms are regulated translationally in prenatal neocortices, including mRNAs encoding RBPs. Here, we show that isoforms of the RBP, Hu antigen D (HuD), regulate the balance of neocortical glutamatergic neurons in an isoform-specific manner during development. HuD3 promoted a Cdp+ intracortically projecting neuronal fate, while HuD4 promoted a Tle4+ subcortically projecting neuronal fate. In early neurogenic radial glia of the neocortex, HuD transcripts were bound and translationally repressed by another RBP, CUG triplet repeat RNA-binding protein 1 (Cugbp1). Cugbp1 knockdown increased the number of Cdp+ intracortically projecting neurons, while having distinct effects on Tle4+ and Ctip2+ subcortically projecting neurons. Neurotrophin-3 promoted HuD3 mRNA translation and Cdp+ fate, which was reversed by Cugbp1. Thus, our findings reveal a novel post-transcriptional molecular pathway in the developing neocortex that regulates the balance of distinct subpopulations of neocortical projection neurons.

2017-09-08 | GSE77647 | GEO

Intestinal epithelial HuR balances counteracting RNA networks to protect against intestinal inflammation and cancer: PART1 Translation profiling

Project description:Elavl1/HuR is a ubiquitous and conserved RNA-binding protein that binds to a U-rich RNA motif that shuttles between nucleus and cytoplasm. In epithelia, the elevated expression of HuR assumingly promotes degeneration and cancer suggesting that its generic suppression may provide clinical benefits. In this study we focused on biological and clinical functions of HuR in intestinal epithelial cells and we presented evidence that changes in HuR levels induce polarized distortions in these cells to support different pathologic outcomes. For translation profiling cytoplasmic fractions of CMT93 sublines, containing monosomes and polysomes were separated as in (Katsanou et al., 2009). Fractions containing monosomes and polysomes were collected using a retriever 500 fraction collector (Teledyne Isco). Monosomal and polysomal fractions were pooled and total RNA was extracted from each fraction using Trizol reagent (Invitrogen). For micorarrays, RNAs were further purified via columns (Qiagen). Biotinylated complementary RNAs,(cRNAs) were hybridized onto Affymetrix Gene Mo-Gene-1.0 Chip in accordance to the protocols of the Genomics Unit of BSRC “Alexander Fleming”. (http://www.fleming.gr/facilities/genomics).

2020-07-01 | E-MTAB-4016 | biostudies-arrayexpress

Embryonic neocortical HuR-immunoprecipitated mRNAs

Project description:Forkhead-box domain (Fox) containing family members are known autism spectrum associated genes. Here we show that, within the developing neocortex, the distinct phospho-states of a single RNA-binding protein, Hu antigen R, dictate mRNA translation and are sufficient to define distinct Foxp-characterized subpopulations of neocortical projection neurons. This demonstrates the importance of HuR phospho-states within the framework of the developing brain and further confirms the role of mRNA translation in autism pathogenesis.

2016-07-08 | GSE77712 | GEO

Mus musculus

Project description:Embryonic neocortical HuR-immunoprecipitated mRNAs

| PRJNA311269 | ENA

A genome-wide CRISPR screen identifies HuR as a regulator of apoptosis induced by dsRNA and viral infection

Project description:Cell death is an important host defense in response to viral infections. In this study,we performed an unbiased whole-genome CRISPR/Cas9 screen in A549 lung adenocarcinoma cells to identify potential regulators involved in cell death triggered dsRNA, a common byproduct of viral replication. Of several top candidate genes, we identified the RNA binding protein ELAV like protein 1 (ELAVL1) (ELAVL1, also called HuR) that encodes Hu antigen R (HuR). Depletion of HuR by gene editing led to less cell death induced by dsRNA. We further demonstrated that HuR regulated apoptosis, and the RNA recognition motif (RRM) 3 of HuR was essential for its proapoptotic function. HuR bound mRNA of anti-apoptotic gene BCL2. HuR depletion had no influence on BCL2 mRNA levels, but instead downregulated the BCL2 translation. Polysome fractionation studies showed that HuR retarded the BCL2 mRNA in the non-translating pool of polysomes. Moreover, protection from dsRNA-induced apoptosis by HuR depletion required the presence of BCL2, indicating that the proapoptotic function of HuR is executed by suppressing BCL2. Consistently, HuR regulated apoptosis induced by infection of encephalomyocarditis or Semliki Forest virus, two unrelated positive strand RNA viruses. Collectively, our work identified a suite of proteins that regulate dsRNA-induced cell death, and elucidated the mechanism by which HuR acts as a pro-apoptotic factor.

2021-01-28 | GSE165625 | GEO

snRNAseq in human fetal neocortex

Project description:Abnormalities in neocortical and synaptic development have been associated with neurodevelopmental disorders. However, the molecular and cellular mechanisms regulating the formation of the initial synapses in an evolutionary advanced neocortical layer, the subplate (SP), are poorly understood. Our snRNAseq screen of human prefrontal neocortices from early (11/12 PCW), mid (14/15 PCW) to late (17/18 PCW) fetal developmental stages revealed the bipartite-to-tripartite differentiation of SP neuronal subclasses. Using polysome profiling with RNAseq, we report for the first time a set of mRNAs undergoing translational control in cellular subclasses of developing human prefrontal neocortices, including SP neurons. By examining both mouse and human neocortex, we further found that an autism spectrum disorder (ASD)-risk gene and RNA binding protein CUGBP Elav-Like Family Member 4 (CELF4) is selectively expressed in the neurons of two synapse-enriched compartments, the SP and the marginal zone. Furthermore, CELF4 binds mRNA targets that are encoded by the synaptic genes associated with ASD and adverse neurodevelopmental outcomes; albeit in an evolutionarily advanced fashion between mouse and human synaptic mRNAs. The selective forebrain Celf4 deletion from developing mouse cortical neurons disrupts the balance of SP synapses in a gender-specific fashion. Taken together, our results underscore the importance of RNA binding proteins and mRNA translation in evolutionarily advanced synaptic development, as well as their possible contribution to gender specific protein synthesis and vulnerability.

2023-08-07 | GSE214532 | GEO

Mouse Celf4 cKO fetal neocortex polysome fractions

2023-08-07 | GSE214328 | GEO

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