Celf4 controls mRNA translation underlying synaptic development in the prenatal mammalian neocortex

Iva Salamon, Yongkyu Park, Terezija Miškić, Janja Kopić, Paul Matteson, Nicholas F. Page, Alfonso Roque, Geoffrey W. McAuliffe, John Favate, Marta Garcia-Forn, Premal Shah, Miloš Judaš, James H. Millonig, Ivica Kostović, Silvia Rubeis, Ronald P. Hart, Željka Krsnik () and Mladen-Roko Rasin ()
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Iva Salamon: Rutgers University, Robert Wood Johnson Medical School
Yongkyu Park: Rutgers University, Robert Wood Johnson Medical School
Terezija Miškić: University of Zagreb, School of Medicine
Janja Kopić: University of Zagreb, School of Medicine
Paul Matteson: Rutgers Robert Wood Johnson Medical School
Nicholas F. Page: Rutgers University, Robert Wood Johnson Medical School
Alfonso Roque: Rutgers University, Robert Wood Johnson Medical School
Geoffrey W. McAuliffe: Rutgers University, Robert Wood Johnson Medical School
John Favate: Rutgers University
Marta Garcia-Forn: Icahn School of Medicine at Mount Sinai
Premal Shah: Rutgers University
Miloš Judaš: University of Zagreb, School of Medicine
James H. Millonig: Rutgers Robert Wood Johnson Medical School
Ivica Kostović: University of Zagreb, School of Medicine
Silvia Rubeis: Icahn School of Medicine at Mount Sinai
Ronald P. Hart: The State University of New Jersey
Željka Krsnik: University of Zagreb, School of Medicine
Mladen-Roko Rasin: Rutgers University, Robert Wood Johnson Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract Abnormalities in neocortical and synaptic development are linked to neurodevelopmental disorders. However, the molecular and cellular mechanisms governing initial synapse formation in the prenatal neocortex remain poorly understood. Using polysome profiling coupled with snRNAseq on human cortical samples at various fetal phases, we identify human mRNAs, including those encoding synaptic proteins, with finely controlled translation in distinct cell populations of developing frontal neocortices. Examination of murine and human neocortex reveals that the RNA binding protein and translational regulator, CELF4, is expressed in compartments enriched in initial synaptogenesis: the marginal zone and the subplate. We also find that Celf4/CELF4-target mRNAs are encoded by risk genes for adverse neurodevelopmental outcomes translating into synaptic proteins. Surprisingly, deleting Celf4 in the forebrain disrupts the balance of subplate synapses in a sex-specific fashion. This highlights the significance of RNA binding proteins and mRNA translation in evolutionarily advanced synaptic development, potentially contributing to sex differences.

Date: 2023
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DOI: 10.1038/s41467-023-41730-8

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