open access publication

Article, 2024

Gene regulatory landscape of cerebral cortex folding

Science Advances, ISSN 2375-2548, Volume 10, 23, Page eadn1640, 10.1126/sciadv.adn1640

Contributors

Singh, Aditi 0000-0001-7438-2863 [1] Del-Valle-Anton, Lucia 0000-0003-1818-3055 [2] De Juan Romero, Camino 0000-0001-7890-8447 [2] Zhang, Ziyi [1] Ortuño, Eduardo Fernández 0000-0001-9414-3392 [2] Mahesh, Arun [1] [3] Espinós, Alexandre 0000-0002-7942-082X [2] Soler, Rafael 0000-0003-1245-5734 [2] Cárdenas, Adrián 0000-0001-5532-4481 [2] Fernández, Virginia 0000-0001-6476-6134 [2] Lusby, Ryan [1] Tiwari, Vijay Kumar 0000-0003-0292-6635 (Corresponding author) [1] [3] [4] Borrell, Vı Ctor 0000-0002-7833-3978 (Corresponding author) [2]

Affiliations

  1. [1] Queen's University Belfast
    2. [NORA names: United Kingdom; Europe, Non-EU; OECD];
  2. [2] Instituto de Neurociencias de Alicante
    3. [NORA names: Spain; Europe, EU; OECD];
  3. [3] University of Southern Denmark
    4. [NORA names: SDU University of Southern Denmark; University; Denmark; Europe, EU; Nordic; OECD];
  4. [4] Odense University Hospital
    5. [NORA names: Region of Southern Denmark; Hospital; Denmark; Europe, EU; Nordic; OECD]

Abstract

Folding of the cerebral cortex is a key aspect of mammalian brain development and evolution, and defects are linked to severe neurological disorders. Primary folding occurs in highly stereotyped patterns that are predefined in the cortical germinal zones by a transcriptomic protomap. The gene regulatory landscape governing the emergence of this folding protomap remains unknown. We characterized the spatiotemporal dynamics of gene expression and active epigenetic landscape (H3K27ac) across prospective folds and fissures in ferret. Our results show that the transcriptomic protomap begins to emerge at early embryonic stages, and it involves cell-fate signaling pathways. The H3K27ac landscape reveals developmental cell-fate restriction and engages known developmental regulators, including the transcription factor Cux2. Manipulating Cux2 expression in cortical progenitors changed their proliferation and the folding pattern in ferret, caused by selective transcriptional changes as revealed by single-cell RNA sequencing analyses. Our findings highlight the key relevance of epigenetic mechanisms in defining the patterns of cerebral cortex folding.

Keywords

H3K27ac, H3K27ac landscape, RNA sequencing analysis, analysis, brain development, cerebral cortex, cerebral cortex folding, changes, cortex, cortex folding, cortical germinal zone, cortical progenitors, defects, development, developmental regulation, disorders, dynamics of gene expression, early embryonic stages, embryonic stages, emergency, epigenetic landscape, epigenetic mechanisms, evolution, expression, findings, fissure, folding, folding pattern, gene expression, gene regulatory landscape, genes, germinal zone, landscape, mammalian brain development, mechanism, neurological disorders, pathway, patterns, primary folds, progenitors, proliferation, protomap, regulation, regulatory landscape, relevance, relevance of epigenetic mechanisms, restriction, results, sequence analysis, signaling pathway, single-cell RNA sequencing analysis, spatiotemporal dynamics, spatiotemporal dynamics of gene expression, stage, stereotyped pattern, transcription, transcription factor <i>, transcriptional changes, zone

Funders

  • European Research Council
  • Deutsche Forschungsgemeinschaft
  • Danish National Research Foundation
  • CaixaBank (Spain)
  • Novo Nordisk (Denmark)

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