Conserved transcriptional regulation by BRN1 and BRN2 in neocortical progenitors drives mammalian neural specification and neocortical expansion

Soraia Barão (), Yijun Xu, José P. Llongueras, Rachel Vistein, Loyal Goff, Kristina J. Nielsen, Byoung-Il Bae, Richard S. Smith, Christopher A. Walsh, Genevieve Stein-O’Brien and Ulrich Müller ()
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Soraia Barão: Johns Hopkins University School of Medicine
Yijun Xu: Johns Hopkins University School of Medicine
José P. Llongueras: Johns Hopkins University School of Medicine
Rachel Vistein: Johns Hopkins University School of Medicine
Loyal Goff: Johns Hopkins University School of Medicine
Kristina J. Nielsen: Johns Hopkins University School of Medicine
Byoung-Il Bae: University of Connecticut School of Medicine
Richard S. Smith: Department of Pharmacology
Christopher A. Walsh: Harvard Medical School
Genevieve Stein-O’Brien: Johns Hopkins University School of Medicine
Ulrich Müller: Johns Hopkins University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract The neocortex varies in size and complexity among mammals due to the tremendous variability in the number and diversity of neuronal subtypes across species. The increased cellular diversity is paralleled by the expansion of the pool of neocortical progenitors and the emergence of indirect neurogenesis during brain evolution. The molecular pathways that control these biological processes and are disrupted in neurological disorders remain largely unknown. Here we show that the transcription factors BRN1 and BRN2 have an evolutionary conserved function in neocortical progenitors to control their proliferative capacity and the switch from direct to indirect neurogenesis. Functional studies in mice and ferrets show that BRN1/2 act in concert with NOTCH and primary microcephaly genes to regulate progenitor behavior. Analysis of transcriptomics data from genetically modified macaques provides evidence that these molecular pathways are conserved in non-human primates. Our findings thus demonstrate that BRN1/2 are central regulators of gene expression programs in neocortical progenitors critical to determine brain size during evolution.

Date: 2024
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DOI: 10.1038/s41467-024-52443-x

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