Sox18 induces development of the lymphatic vasculature in mice

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 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.

The lymphangiogenic factor SOX 18: A key indicator to stage gastric tumor progression

“…[19][20][21][22][23][24][25][26][27][28][29][30] In fact, few studies have revealed the significance of SOX group F gene expression in human cancer, although cell line-based studies have demonstrated that both SOX 18 and SOX 7 were highly expressed in several strains of gastric, pancreatic and esophageal cancer cell lines. 22,32 In the present study, SOX group F gene expression determined by RT-PCT was increased in gastric cancer tissues than in normal gastric tissues obtained from the same individuals.…”

“…23,24 Thus, interfering with SOX 18 function, both blood vessel formation and subsequent tumor growth are inhibited and this process is responsible for the lymphatic defect in hypotrichosis-lymphoedema-telangiectasia. [25][26][27][28] The SOX 7 and SOX 17 genes are also known to have compensatory roles during angiogenesis and lymphangiogenesis. [19][20][21] It has been demonstrated that blood circulation in SOX 7 and SOX 18 double knock-down zebrafish was blocked in the trunk and tail due to multiple fusions between the axial vessels.…”

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

“…SRY-related HMG-box 18 (Sox18), a member of the F-group of Sox transcription factors, has been identified to bind upstream of PROX1 and up-regulate Prox1 expression (François et al 2008). Moreover, mice carrying a natural Sox18-dominant-negative mutation fail to initiate Prox1 up-regulation in venous endothelial cells during development and to develop a normal lymphatic system (François et al 2008).…”

“…SRY-related HMG-box 18 (Sox18), a member of the F-group of Sox transcription factors, has been identified to bind upstream of PROX1 and up-regulate Prox1 expression (François et al 2008). Moreover, mice carrying a natural Sox18-dominant-negative mutation fail to initiate Prox1 up-regulation in venous endothelial cells during development and to develop a normal lymphatic system (François et al 2008). Importantly, humans with mutations in Sox18 develop a blood/lymphatic vascular disease, hypotrichosis-lymphedematelangiectasia (HLT), which is characterized by alopecia, hemorrhage, and lymphedema (Irrthum et al 2003).…”

Studies on Axenfeld–Rieger syndrome patients and mice reveal Foxc1's role in corneal neovascularization

“…1C, Ra Op/+ ). The Ra Op mutant mice carry a natural mutation in the Sox18 [SRY (sex determining region Y) box 18] gene (11,12) that triggers the production of a truncated nonfunctional protein that suppresses F-group SOX (Sox7, Sox17, and Sox18) proteins in blood vessels. During lymphangiogenesis, Sox18 is expressed in venous cells to induce Prox-1 expression (11); at the same embryonic stages, Foxc1 and Foxc2 are required to maintain artery vs. vein specification (13).…”