PUBLICATION

Multiple cis-regulatory elements control prox1a expression in distinct lymphatic vascular beds

Authors
Panara, V., Yu, H., Peng, D., Staxäng, K., Hodik, M., Filipek-Gorniok, B., Kazenwadel, J., Skoczylas, R., Mason, E., Allalou, A., Harvey, N.L., Haitina, T., Hogan, B.M., Koltowska, K.
ID
ZDB-PUB-240510-14
Date
2024
Source
Development (Cambridge, England)   151(9): (Journal)
Registered Authors
Haitina, Tatjana, Hogan, Ben M., Mason, Elizabeth, Panara, Virginia, Yu, Hujun
Keywords
Enhancers, Evolutionary conservation, Gene regulation, Lymphatic endothelial cell, Prox1, Transcription factor, Zebrafish
MeSH Terms
  • Homeodomain Proteins*/genetics
  • Homeodomain Proteins*/metabolism
  • Tumor Suppressor Proteins*/genetics
  • Tumor Suppressor Proteins*/metabolism
  • Promoter Regions, Genetic/genetics
  • CRISPR-Cas Systems/genetics
  • Zebrafish*/embryology
  • Zebrafish*/genetics
  • Gene Expression Regulation, Developmental*
  • Endothelial Cells*/metabolism
  • Mice
  • Lymphatic Vessels*/embryology
  • Lymphatic Vessels*/metabolism
  • Lymphangiogenesis/genetics
  • Enhancer Elements, Genetic*/genetics
  • Animals
  • Zebrafish Proteins*/genetics
  • Zebrafish Proteins*/metabolism
(all 18)
PubMed
38722096 Full text @ Development
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.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
nim5TgTransgenic Insertion
    nub47Tg
      		Transgenic Insertion
        nz101TgTransgenic Insertion
          s916TgTransgenic Insertion
            uq4bh
              		Point Mutation
              y7TgTransgenic Insertion
                1 - 6 of 6
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                Human Disease / Model
                No data available
                Sequence Targeting Reagents
                Target Reagent Reagent Type
                prox1aCRISPR2-prox1aCRISPR
                prox1aCRISPR3-prox1aCRISPR
                1 - 2 of 2
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                Fish
                No data available
                Antibodies
                Name Type Antigen Genes Isotypes Host Organism
                Ab5-prox1polyclonalIgGRabbit
                1 - 1 of 1
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                Orthology
                No data available
                Engineered Foreign Genes
                Marker Marker Type Name
                DsRedEFGDsRed
                EGFPEFGEGFP
                KALTA4EFGKALTA4
                mCherryEFGmCherry
                TagRFPEFGTagRFP
                1 - 5 of 5
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                Mapping
                No data available
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                Citation
                Panara, V., Yu, H., Peng, D., Staxäng, K., Hodik, M., Filipek-Gorniok, B., Kazenwadel, J., Skoczylas, R., Mason, E., Allalou, A., Harvey, N.L., Haitina, T., Hogan, B.M., Koltowska, K. (2024) Multiple cis-regulatory elements control prox1a expression in distinct lymphatic vascular beds. Development (Cambridge, England). 151(9):.