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Vol. 18, Issue 4, 1421-1429, April 2007

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Prox1 Induces Lymphatic Endothelial Differentiation via Integrin 9 and Other Signaling Cascades

Koichi Mishima^*,, Tetsuro Watabe^*, Akira Saito^*, Yasuhiro Yoshimatsu^*, Natsuko Imaizumi^*, Shinji Masui, Masanori Hirashima, Tohru Morisada, Yuichi Oike, Makoto Araie, Hitoshi Niwa, Hajime Kubo^||, Toshio Suda, and Kohei Miyazono^*,¶

Departments of *Molecular Pathology and Ophthalmology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan; Laboratory for Pluripotent Cell Studies, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan; Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Shinanomachi, Tokyo 160-8582, Japan; ^||Molecular and Cancer Research Unit, Horizontal Medical Research Organization (HMRO), Graduate School of Medicine, Kawaramachi, Kyoto University, Kyoto 606-8501, Japan; and ^¶Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Ariake, Tokyo 135-8550, Japan

Submitted September 5, 2006; Revised January 2, 2007; Accepted January 31, 2007
Monitoring Editor: Ben Margolis

During embryonic lymphatic development, a homeobox transcription factor Prox1 plays important roles in sprouting and migration of a subpopulation of blood vessel endothelial cells (BECs) toward VEGF-C–expressing cells. However, effects of Prox1 on endothelial cellular behavior remain to be elucidated. Here, we show that Prox1, via induction of integrin 9 expression, inhibits sheet formation and stimulates motility of endothelial cells. Prox1-expressing BECs preferentially migrated toward VEGF-C via up-regulation of the expression of integrin 9 and VEGF receptor 3 (VEGFR3). In mouse embryos, expression of VEGFR3 and integrin 9 is increased in Prox1-expressing lymphatic endothelial cells (LECs) compared with BECs. Knockdown of Prox1 expression in human LECs led to decrease in the expression of integrin 9 and VEGFR3, resulting in the decreased chemotaxes toward VEGF-C. These findings suggest that Prox1 plays important roles in conferring and maintaining the characteristics of LECs by modulating multiple signaling cascades and that integrin 9 may function as a key regulator of lymphangiogenesis acting downstream of Prox1.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Kohei Miyazono (miyazono-ind{at}umin.ac.jp)

Abbreviations used: EC, endothelial cell; ESC, embryonic stem cell; PECAM1, platelet-endothelial cell adhesion molecule 1; SMA, - smooth muscle actin; VEGF, vascular endothelial growth factor; BEC, blood vascular endothelial cell; LEC, lymphatic endothelial cell.

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