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Cited by 55RNA Research and SplicingRNA and protein synthesis mechanismsGenetics and Neurodevelopmental Disorders

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

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Popovitchenko, Tatiana, Park, Yongkyu, Page, Nicholas F., Luo, Xiaobing, Krsnik, Zeljka, Liu, Yuan, Salamon, Iva, Stephenson, Jessica D. +18 more·2020·Nature Communications
DOI 10.1038/s41467-020-15412-8PMC PMC7125149
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Abstract

Neurodevelopment requires precise regulation of gene expression, including post-transcriptional 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.

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  • ELAVL4 expression decreases self-renewal of neural progenitor cells and promotes deep-layer glutamatergic neuronal differentiation.

    “ELAVL4 expression decreases self-renewal of neural progenitor cells and promotes deep-layer glutamatergic neuronal differentiation (Akamatsu et al., 2005; DeBoer et al., 2014; Popovitchenko et al., 2020).”

    From ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids (2021) · cites this paper as Popovitchenko et al., 2020

    The Results section, “Elavl4-v3 promotes lower layer (LL) identity when not repressed in RG” (page unavailable), reports that premature Elavl4-v3 expression in radial glia increased a lower-layer neuronal identity marker, supporting the differentiation part of the claim. It does not establish that ELAVL4 expression decreases neural progenitor self-renewal; the Results section, “Celf1 regulates the balance of glutamatergic neurons” (page unavailable), instead reports greater progenitor retention in a condition with increased Elavl4 protein. (LLM, conf=0.86)

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Authors
Popovitchenko, T., Park, Y., Page, N. F., Luo, X., Krsnik, Z., Liu, Y., Salamon, I., Stephenson, J. D., Kraushar, M. L., Volk, N. L., Patel, S. M., Wijeratne, H. R. S., Li, D., Suthar, K. S., Wach, A., Sun, M., Arnold, S. J., Akamatsu, W., Okano, H., Paillard, L., Zhang, H., Buyske, S., Kostovic, I., De Rubeis, S., Hart, R. P., & Rasin, M.-R.
Affiliations
  • Rutgers, The State University of New Jersey (US)
  • University of Freiburg (DE)
  • Keio University (JP)
  • Centre National de la Recherche Scientifique (FR)
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-04-03
Volume
11
Issue
1
Pages
1674-1674
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-15412-8
PMC
PMC7125149
OpenAlex
W3015005771
Cited by
55
References
13
Citations by year
2026: 6 · 2025: 6 · 2024: 10 · 2023: 10 · 2022: 9 · 2021: 10 · 2020: 4
FWCI
2.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
  • Rutgers University Community Repository (Rutgers University) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Defense (W81XQH-18-1-0338)
  • Beatrice and Samuel A. Seaver Foundation
  • U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NS064303, NS075367)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
ELAVL4, CELF1, RNA-binding proteins, post-transcriptional regulation, neocortical neurogenesis, glutamatergic neurons, neurodevelopmental disorders, mRNA isoforms, polysomes
MeSH terms
ELAV-Like Protein 4, CELF1 Protein, RNA-Seq, Animals, Female, Male, Mice, Transgenic, Neuroglia, Neurons, Polyribosomes, Protein Biosynthesis, Alternative Splicing, Gene Expression Regulation, Developmental, Glutamic Acid, Neocortex, 5' Untranslated Regions, Cell Line, Tumor, Mice, Neurogenesis, Neural Stem Cells, RNA Isoforms, Primary Cell Culture

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