TY - JOUR
T1 - Translational derepression of Elavl4 isoforms at their alternative 5′ UTRs determines neuronal development
AU - Popovitchenko, Tatiana
AU - Park, Yongkyu
AU - Page, Nicholas F.
AU - Luo, Xiaobing
AU - Krsnik, Zeljka
AU - Liu, Yuan
AU - Salamon, Iva
AU - Stephenson, Jessica D.
AU - Kraushar, Matthew L.
AU - Volk, Nicole L.
AU - Patel, Sejal M.
AU - Wijeratne, H. R.Sagara
AU - Li, Diana
AU - Suthar, Kandarp S.
AU - Wach, Aaron
AU - Sun, Miao
AU - Arnold, Sebastian J.
AU - Akamatsu, Wado
AU - Okano, Hideyuki
AU - Paillard, Luc
AU - Zhang, Huaye
AU - Buyske, Steven
AU - Kostovic, Ivica
AU - De Rubeis, Silvia
AU - Hart, Ronald P.
AU - Rasin, Mladen Roko
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH) grants (NS064303 and NS075367) and Robert Wood Johnson Medical School start-up funds (M.R.R). This work was also supported in part by the Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, through the Epilepsy Research Program under Award No. W81XQH-18-1-0338 to H.Z. and M.R.R. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. In addition, this work was supported in part by the “Research Cooperability“ Program of the Croatian Science Foundation funded by the European Union from the European Social Fund under the Operational Programme Efficient Human Resources 2014-2020 PSZ-2019-02-4710 to Z.K. and M.R.R. This publication was also supported by Adris Foundation (ZK), Croatian Science Foundation projects CSF-IP-09-2014-4517 (IK) and co-financed by the Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience (project “Experimental and clinical research of hypoxic-ischemic damage in perinatal and adult brain”; GA KK01.1.1.01.0007 funded by the European Union through the European Regional Development Fund), and NIH grant NS089578 to HZ. N.F.P. received support from the Aresty Undergraduate Research Fellowship and the Thermo Fisher Scientific Antibody Scholarship Program. J.D.S. was funded by an Undergraduate Research Award from the Rutgers Honors College-New Brunswick. M.L.K. was supported by a NIH NRSA F30 MD/PhD Fellowship (1F30MH106220). S.D.R. is supported by the Beatrice and Samuel A. Seaver Foundation and the Fascitelli Research Scholar Award. This study was supported by the Germany’s Excellence Strategy (CIBSS–EXC-2189– Project ID 390939984) to S.J.A. We thank Ishan Khosla for help with text editing, and Erik DeBoer, Aditi Dubey, Althea Stillman, Elizaveta Muravieva, Jack Pike, Faizan Rafi, and Midori Lofton for technical support, Dr. Paola Arlotta (Harvard University) for sharing the Cdk5r construct, Dr. Grigori Enikolopov (Stony Brook University) for Nestin-GFP mice, Drs. Lori Covey (Rutgers University) and Mengqing Xiang (Rutgers University) for luminometer usage, and Dr. Paul Copeland for microultracentrifuge usage.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85083041104&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-15412-8
DO - 10.1038/s41467-020-15412-8
M3 - Article
C2 - 32245946
AN - SCOPUS:85083041104
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1674
ER -