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

Tatiana Popovitchenko, Yongkyu Park, Nicholas F. Page, Xiaobing Luo, Zeljka Krsnik, Yuan Liu, Iva Salamon, Jessica D. Stephenson, Matthew L. Kraushar, Nicole L. Volk, Sejal M. Patel, H. R.Sagara Wijeratne, Diana Li, Kandarp S. Suthar, Aaron Wach, Miao Sun, Sebastian J. Arnold, Wado Akamatsu, Hideyuki Okano, Luc PaillardHuaye Zhang, Steven Buyske, Ivica Kostovic, Silvia De Rubeis, Ronald P. Hart, Mladen Roko Rasin

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number1674
JournalNature communications
Volume11
Issue number1
DOIs
Publication statusPublished - 2020 Dec 1

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    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., ... Rasin, M. R. (2020). Translational derepression of Elavl4 isoforms at their alternative 5′ UTRs determines neuronal development. Nature communications, 11(1), [1674]. https://doi.org/10.1038/s41467-020-15412-8