Sox18 induces development of the lymphatic vasculature in mice

Francois, Mathias, Caprini, Andrea, Hosking, Brett, Orsenigo, Fabrizio, Wilhelm, Dagmar, Browne, Catherine, Paavonen, Karri, Karnezis, Tara, Shayan, Ramin, Downes, Meredith, Davidson, Tara, Tutt, Desmond, Cheah, Kathryn S. E., Stacker, Steven A., Muscat, George E. O., Achen, Marc G., Dejana, Elisabetta and Koopman, Peter (2008) Sox18 induces development of the lymphatic vasculature in mice. Nature, 456 7222: 643-647. doi:10.1038/nature07391

Author Francois, Mathias
Caprini, Andrea
Hosking, Brett
Orsenigo, Fabrizio
Wilhelm, Dagmar
Browne, Catherine
Paavonen, Karri
Karnezis, Tara
Shayan, Ramin
Downes, Meredith
Davidson, Tara
Tutt, Desmond
Cheah, Kathryn S. E.
Stacker, Steven A.
Muscat, George E. O.
Achen, Marc G.
Dejana, Elisabetta
Koopman, Peter
Title Sox18 induces development of the lymphatic vasculature in mice
Journal name Nature   Check publisher's open access policy
ISSN 0028-0836
Publication date 2008-12-04
Year available 2008
Sub-type Article (original research)
DOI 10.1038/nature07391
Open Access Status
Volume 456
Issue 7222
Start page 643
End page 647
Total pages 5
Editor Philip Campbell
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject C1
060403 Developmental Genetics (incl. Sex Determination)
Abstract The lymphatic system plays a key role in tissue fluid regulation and tumour metastasis, and lymphatic defects underlie many pathological states including lymphoedema, lymphangiectasia, lymphangioma and lymphatic dysplasia1, 2, 3. However, the origins of the lymphatic system in the embryo, and the mechanisms that direct growth of the network of lymphatic vessels, remain unclear. Lymphatic vessels are thought to arise from endothelial precursor cells budding from the cardinal vein under the influence of the lymphatic hallmark gene Prox1 (prospero homeobox 1; ref. 4). Defects in the transcription factor gene SOX18 (SRY (sex determining region Y) box 18) cause lymphatic dysfunction in the human syndrome hypotrichosis-lymphoedema-telangiectasia5, suggesting that Sox18 may also play a role in lymphatic development or function. Here we use molecular, cellular and genetic assays in mice to show that Sox18 acts as a molecular switch to induce differentiation of lymphatic endothelial cells. Sox18 is expressed in a subset of cardinal vein cells that later co-express Prox1 and migrate to form lymphatic vessels. Sox18 directly activates Prox1 transcription by binding to its proximal promoter. Overexpression of Sox18 in blood vascular endothelial cells induces them to express Prox1 and other lymphatic endothelial markers, while Sox18-null embryos show a complete blockade of lymphatic endothelial cell differentiation from the cardinal vein. Our findings demonstrate a critical role for Sox18 in developmental lymphangiogenesis, and suggest new avenues to investigate for therapeutic management of human lymphangiopathies.
Keyword Lymphatic system
Lymphatic vascular development
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID LSHG-CT-2004-503573
Institutional Status UQ

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