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

Tatiana Popovitchenko (1) , Yongkyu Park (1) , Nicholas F Page (1) , Xiaobing Luo (1) , Zeljka Krsnik (2) , Yuan Liu (1) , Iva Salamon (1, 2) , Jessica D Stephenson (1) , Matthew L Kraushar (1) , 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 (3) , Wado Akamatsu (4) , Hideyuki Okano (4) , Luc Paillard (5) , Huaye Zhang (1) , Steven Buyske (1) , Ivica Kostovic (2) , Silvia de Rubeis (6) , Ronald P Hart (1) , Mladen-Roko Rasin (1)

1 RU - Rutgers, The State University of New Jersey [New Brunswick]
2 University of Zagreb
3 University of Freiburg [Freiburg]
4 Keio University School of Medicine [Tokyo, Japan]
5 IGDR - Institut de Génétique et Développement de Rennes
6 MSSM - Icahn School of Medicine at Mount Sinai [New York]

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.

Domains: Life Sciences [q-bio]

Tatiana Popovitchenko, Yongkyu Park, Nicholas F Page, Xiaobing Luo, Zeljka Krsnik, et al.. Translational derepression of Elavl4 isoforms at their alternative 5' UTRs determines neuronal development. Nature Communications, 2020, 11 (1), pp.1674. ⟨10.1038/s41467-020-15412-8⟩. ⟨hal-02565573⟩