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

Nat Commun. 2020 Apr 3;11(1):1674. doi: 10.1038/s41467-020-15412-8.

Tatiana Popovitchenko ¹ ², Yongkyu Park ¹, Nicholas F Page ¹ ³, Xiaobing Luo ¹, Zeljka Krsnik ⁴, Yuan Liu ¹ ², Iva Salamon ¹ ² ⁴, Jessica D Stephenson ¹, Matthew L Kraushar ¹ ², Nicole L Volk ¹, Sejal M Patel ¹, H R Sagara Wijeratne ¹, Diana Li ¹, Kandarp S Suthar ¹, Aaron Wach ¹, Miao Sun ¹, Sebastian J Arnold ⁵, Wado Akamatsu ⁶, Hideyuki Okano ⁶, Luc Paillard ⁷, Huaye Zhang ¹, Steven Buyske ⁸, Ivica Kostovic ⁴, Silvia De Rubeis ⁹ ¹⁰ ¹¹ ¹², Ronald P Hart ³, Mladen-Roko Rasin ¹³

Affiliations

1 Department of Neuroscience and Cell Biology, Rutgers University, Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA.
2 Graduate Program in Neurosciences, Rutgers University, Piscataway, NJ, 08854, USA.
3 Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, 08854, USA.
4 Croatian Institute for Brain Research, Center of Research Excellence for Basic, Clinical and Translational Neuroscience, University of Zagreb, School of Medicine, Zagreb, 10000, Croatia.
5 Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, Signaling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, D-79104, Germany.
6 Department of Physiology, Keio University School of Medicine, Tokyo, 160-8582, Japan.
7 Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes)-UMR 6290, F-35000, Rennes, France.
8 Department of Statistics, Rutgers University, Piscataway, NJ, 08854, USA.
9 Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY, 10029, USA.
10 Seaver Autism Center, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
11 Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
12 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
13 Department of Neuroscience and Cell Biology, Rutgers University, Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA. roko.rasin@rutgers.edu.

PMID: 32245946 DOI: 10.1038/s41467-020-15412-8

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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