Multiple cis-regulatory elements control prox1a expression in distinct lymphatic vascular beds
- Author(s)
- Panara, V; Yu, H; Peng, D; Staxäng, K; Hodik, M; Filipek-Gorniok, B; Kazenwadel, J; Skoczylas, R; Mason, E; Allalou, A; Harvey, NL; Haitina, T; Hogan, BM; Koltowska, K;
- Details
- Publication Year 2024-05-01,Volume 151,Issue #9,Page dev202525
- Journal Title
- Development
- Publication Type
- Research article
- Abstract
- During embryonic development, lymphatic endothelial cell (LEC) precursors are distinguished from blood endothelial cells by the expression of Prospero-related homeobox 1 (Prox1), which is essential for lymphatic vasculature formation in mouse and zebrafish. Prox1 expression initiation precedes LEC sprouting and migration, serving as the marker of specified LECs. Despite its crucial role in lymphatic development, Prox1 upstream regulation in LECs remains to be uncovered. SOX18 and COUP-TFII are thought to regulate Prox1 in mice by binding its promoter region. However, the specific regulation of Prox1 expression in LECs remains to be studied in detail. Here, we used evolutionary conservation and chromatin accessibility to identify enhancers located in the proximity of zebrafish prox1a active in developing LECs. We confirmed the functional role of the identified sequences through CRISPR/Cas9 mutagenesis of a lymphatic valve enhancer. The deletion of this region results in impaired valve morphology and function. Overall, our results reveal an intricate control of prox1a expression through a collection of enhancers. Ray-finned fish-specific distal enhancers drive pan-lymphatic expression, whereas vertebrate-conserved proximal enhancers refine expression in functionally distinct subsets of lymphatic endothelium.
- Publisher
- The Company of Biologists
- Keywords
- Animals; *Homeodomain Proteins/metabolism/genetics; *Zebrafish/genetics/embryology; *Tumor Suppressor Proteins/metabolism/genetics; *Gene Expression Regulation, Developmental; *Enhancer Elements, Genetic/genetics; *Lymphatic Vessels/metabolism/embryology; *Zebrafish Proteins/metabolism/genetics; *Endothelial Cells/metabolism; Lymphangiogenesis/genetics; CRISPR-Cas Systems/genetics; Promoter Regions, Genetic/genetics; Mice; Enhancers; Evolutionary conservation; Gene regulation; Lymphatic endothelial cell; Prox1; Transcription factor; Zebrafish
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.1242/dev.202525
- Open Access at Publisher's Site
https://doi.org/10.1242/dev.202525- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-07-17 04:32:34
Last Modified: 2024-07-17 04:35:46