Conserved enhancers control notochord expression of vertebrate Brachyury

Cassie L. Kemmler, Jana Smolikova, Hannah R. Moran, Brandon J. Mannion, Dunja Knapp, Fabian Lim, Anna Czarkwiani, Viviana Hermosilla Aguayo, Vincent Rapp, Olivia E. Fitch, Seraina Bötschi, Licia Selleri, Emma Farley, Ingo Braasch, Maximina Yun, Axel Visel, Marco Osterwalder, Christian Mosimann, Zbynek Kozmik () and Alexa Burger ()
Additional contact information
Cassie L. Kemmler: University of Colorado Anschutz Medical Campus
Jana Smolikova: Institute of Molecular Genetics of the ASCR, v. v. i.
Hannah R. Moran: University of Colorado Anschutz Medical Campus
Brandon J. Mannion: Lawrence Berkeley National Laboratory
Dunja Knapp: CRTD Center for Regenerative Therapies Dresden
Fabian Lim: University of California San Diego
Anna Czarkwiani: CRTD Center for Regenerative Therapies Dresden
Viviana Hermosilla Aguayo: University of California San Francisco
Vincent Rapp: University of Bern
Olivia E. Fitch: Michigan State University
Seraina Bötschi: University of Zurich
Licia Selleri: University of California San Francisco
Emma Farley: University of California San Diego
Ingo Braasch: Michigan State University
Maximina Yun: CRTD Center for Regenerative Therapies Dresden
Axel Visel: Lawrence Berkeley National Laboratory
Marco Osterwalder: Lawrence Berkeley National Laboratory
Christian Mosimann: University of Colorado Anschutz Medical Campus
Zbynek Kozmik: Institute of Molecular Genetics of the ASCR, v. v. i.
Alexa Burger: University of Colorado Anschutz Medical Campus

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract The cell type-specific expression of key transcription factors is central to development and disease. Brachyury/T/TBXT is a major transcription factor for gastrulation, tailbud patterning, and notochord formation; however, how its expression is controlled in the mammalian notochord has remained elusive. Here, we identify the complement of notochord-specific enhancers in the mammalian Brachyury/T/TBXT gene. Using transgenic assays in zebrafish, axolotl, and mouse, we discover three conserved Brachyury-controlling notochord enhancers, T3, C, and I, in human, mouse, and marsupial genomes. Acting as Brachyury-responsive, auto-regulatory shadow enhancers, in cis deletion of all three enhancers in mouse abolishes Brachyury/T/Tbxt expression selectively in the notochord, causing specific trunk and neural tube defects without gastrulation or tailbud defects. The three Brachyury-driving notochord enhancers are conserved beyond mammals in the brachyury/tbxtb loci of fishes, dating their origin to the last common ancestor of jawed vertebrates. Our data define the vertebrate enhancers for Brachyury/T/TBXTB notochord expression through an auto-regulatory mechanism that conveys robustness and adaptability as ancient basis for axis development.

Date: 2023
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DOI: 10.1038/s41467-023-42151-3

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