Sox18 induces development of the lymphatic vasculature in mice.

[lymphedemapeople]

Sox18 induces development of the lymphatic vasculature in mice.

Nature. 2008 Oct 19

François M, Caprini A, Hosking B, Orsenigo F, Wilhelm D, Browne C,
Paavonen K, Karnezis T, Shayan R, Downes M, Davidson T, Tutt D, Cheah
KS, Stacker SA, Muscat GE, Achen MG, Dejana E, Koopman P.
Institute for Molecular Bioscience, The University of Queensland,
Brisbane, Queensland 4072, Australia.

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 dysplasia. 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-telangiectasia,
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.

http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature07391.html