학술논문
Conserved enhancers control notochord expression of vertebrate Brachyury.
Document Type
article
Author
Kemmler, Cassie; Smolikova, Jana; Moran, Hannah; Mannion, Brandon; Knapp, Dunja; Lim, Fabian; Czarkwiani, Anna; Hermosilla Aguayo, Viviana; Rapp, Vincent; Fitch, Olivia; Bötschi, Seraina; Braasch, Ingo; Yun, Maximina; Mosimann, Christian; Kozmik, Zbynek; Burger, Alexa; Selleri, Licia; Farley, Emma; Visel, Axel; Osterwalder, Marco
Source
Nature Communications. 14(1)
Subject
Language
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.