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 Paillard, Huaye Zhang, Steven Buyske, Ivica Kostovic, Silvia De Rubeis, Ronald P. Hart and Mladen-Roko Rasin ()
Additional contact information
Tatiana Popovitchenko: Rutgers University, Robert Wood Johnson Medical School
Yongkyu Park: Rutgers University, Robert Wood Johnson Medical School
Nicholas F. Page: Rutgers University, Robert Wood Johnson Medical School
Xiaobing Luo: Rutgers University, Robert Wood Johnson Medical School
Zeljka Krsnik: Croatian Institute for Brain Research, Center of Research Excellence for Basic, Clinical and Translational Neuroscience, University of Zagreb, School of Medicine
Yuan Liu: Rutgers University, Robert Wood Johnson Medical School
Iva Salamon: Rutgers University, Robert Wood Johnson Medical School
Jessica D. Stephenson: Rutgers University, Robert Wood Johnson Medical School
Matthew L. Kraushar: Rutgers University, Robert Wood Johnson Medical School
Nicole L. Volk: Rutgers University, Robert Wood Johnson Medical School
Sejal M. Patel: Rutgers University, Robert Wood Johnson Medical School
H. R. Sagara Wijeratne: Rutgers University, Robert Wood Johnson Medical School
Diana Li: Rutgers University, Robert Wood Johnson Medical School
Kandarp S. Suthar: Rutgers University, Robert Wood Johnson Medical School
Aaron Wach: Rutgers University, Robert Wood Johnson Medical School
Miao Sun: Rutgers University, Robert Wood Johnson Medical School
Sebastian J. Arnold: Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, Signaling Research Centers BIOSS and CIBSS, University of Freiburg
Wado Akamatsu: Department of Physiology, Keio University School of Medicine
Hideyuki Okano: Department of Physiology, Keio University School of Medicine
Luc Paillard: Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes)-UMR 6290
Huaye Zhang: Rutgers University, Robert Wood Johnson Medical School
Steven Buyske: Department of Statistics, Rutgers University
Ivica Kostovic: Croatian Institute for Brain Research, Center of Research Excellence for Basic, Clinical and Translational Neuroscience, University of Zagreb, School of Medicine
Silvia De Rubeis: Department of Psychiatry, Icahn School of Medicine at Mount Sinai
Ronald P. Hart: Rutgers University
Mladen-Roko Rasin: Rutgers University, Robert Wood Johnson Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-21

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15412-8

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