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Vol. 17, Issue 2, 576-584, February 2006

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Prox1 Promotes Lineage-specific Expression of Fibroblast Growth Factor (FGF) Receptor-3 in Lymphatic Endothelium: A Role for FGF Signaling in Lymphangiogenesis

Jay W. Shin ^* , Michael Min ^*, Fréderic Larrieu-Lahargue , Xavier Canron , Rainer Kunstfeld ^*, Lynh Nguyen ^*, Janet E. Henderson , Andreas Bikfalvi , Michael Detmar ^* , and Young-Kwon Hong ^* ||

^* Cutaneous Biology Research Center and Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129; Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (Eidgenössische Technische Hochschule Zurich), CH-8092 Zurich, Switzerland; Molecular Angiogenesis Laboratory (Institut National de la Santé et de la Recherche Médicale E 0113), University Bordeaux 1, 33405 Talence, France; ^|| Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089; and Department of Medicine and Centre for Bone and Periodontal Research, McGill University, Montreal, Québec H3A 1A4, Canada

Submitted April 29, 2005; Revised September 26, 2005; Accepted November 5, 2005
Monitoring Editor: Carl-Henrik Heldin

Fibroblast growth factors play important roles in angiogenesis, but their functions in lymphangiogenesis remain poorly understood. The homeodomain transcription factor Prox1 is essential for development of the lymphatic system by specifying lymphatic endothelial cell (LEC) fate. Here, we identify fibroblast growth factor (FGF) receptor (FGFR)-3 as a novel Prox1 target gene. Ectopic overexpression of Prox1 in blood vascular endothelial cells up-regulates FGFR-3. Prox1 induces the expression of the IIIc isoform, which we also found to be the major isoform of FGFR-3 expressed in LECs. This transcriptional activation is mediated by a direct binding of Prox1 to newly identified Prox1-response elements in the FGFR-3 promoter. Consistently, FGFR-3 is up-regulated in Prox1-positive newly formed lymphatic vessels during embryogenesis and its lymphatic-specific expression is maintained throughout development. We also found that FGF-1 and FGF-2 promote proliferation, migration, and survival of cultured LECs without involvement of vascular endothelial cell growth factor receptor-3. We show that FGF-2 binds to low- and high-affinity receptors on LECs and is efficiently internalized and processed. Moreover, functional inhibition of FGFR-3 using small interfering RNA represses LEC proliferation. Together, these results indicate that FGFR-3 is an initial target of Prox1 during the lymphatic cell fate specification and that FGF signaling may play an important role in lymphatic vessel development.

Abbreviations used: BEC, blood vascular endothelial cell; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; LEC, lymphatic vascular endothelial cell; VEGF, vascular endothelial cell growth factor; VEGFR, vascular endothelial cell growth factor receptor.

Address correspondence to: Young-Kwon Hong (young.hong{at}usc.edu).

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