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https://hdl.handle.net/2440/137711
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Type: | Journal article |
Title: | A Prox1 enhancer represses haematopoiesis in the lymphatic vasculature |
Author: | Kazenwadel, J. Venugopal, P. Oszmiana, A. Toubia, J. Arriola-Martinez, L. Panara, V. Piltz, S.G. Brown, C. Ma, W. Schreiber, A.W. Koltowska, K. Taoudi, S. Thomas, P.Q. Scott, H.S. Harvey, N.L. |
Citation: | Nature, 2023; 614(7947):343-348 |
Publisher: | Springer |
Issue Date: | 2023 |
ISSN: | 0028-0836 1476-4687 |
Statement of Responsibility: | Jan Kazenwadel, Parvathy Venugopal, Anna Oszmiana, John Toubia, Luis Arriola-Martinez, Virginia Panara, Sandra G. Piltz, Chris Brown, Wanshu Ma, Andreas W. Schreiber, Katarzyna Koltowska, Samir Taoudi, Paul Q. Thomas, Hamish S. Scott and Natasha L. Harvey |
Abstract: | Transcriptional enhancer elements are responsible for orchestrating the temporal and spatial control over gene expression that is crucial for programming cell identity during development1,2,3. Here we describe a novel enhancer element that is important for regulating the expression of Prox1 in lymphatic endothelial cells. This evolutionarily conserved enhancer is bound by key lymphatic transcriptional regulators including GATA2, FOXC2, NFATC1 and PROX1. Genome editing of the enhancer to remove five nucleotides encompassing the GATA2-binding site resulted in perinatal death of homozygous mutant mice due to profound lymphatic vascular defects. Lymphatic endothelial cells in enhancer mutant mice exhibited reduced expression of genes characteristic of lymphatic endothelial cell identity and increased expression of genes characteristic of haemogenic endothelium, and acquired the capacity to generate haematopoietic cells. These data not only reveal a transcriptional enhancer element important for regulating Prox1 expression and lymphatic endothelial cell identity but also demonstrate that the lymphatic endothelium has haemogenic capacity, ordinarily repressed by Prox1. |
Keywords: | Endothelial Cells Lymphatic Vessels Animals Mice Homeodomain Proteins Transcription Factors Hematopoiesis Enhancer Elements, Genetic |
Description: | Published online: 25 January 2023 |
Rights: | © The Author(s), under exclusive licence to Springer Nature Limited 2023 |
DOI: | 10.1038/s41586-022-05650-9 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1061365 http://purl.org/au-research/grants/nhmrc/1146706 http://purl.org/au-research/grants/arc/DP210103351 http://purl.org/au-research/grants/arc/FT130101254 http://purl.org/au-research/grants/nhmrc/1023059 |
Published version: | http://dx.doi.org/10.1038/s41586-022-05650-9 |
Appears in Collections: | Medicine publications |
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