Prox1 induces lymphatic endothelial differentiation via integrin alpha9 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; Kohei Miyazono

doi:10.1091/mbc.e06-09-0780

Prox1 induces lymphatic endothelial differentiation via integrin alpha9 and other signaling cascades

Mol Biol Cell. 2007 Apr;18(4):1421-9. doi: 10.1091/mbc.e06-09-0780. Epub 2007 Feb 7.

Authors

Koichi Mishima¹, Tetsuro Watabe, Akira Saito, Yasuhiro Yoshimatsu, Natsuko Imaizumi, Shinji Masui, Masanori Hirashima, Tohru Morisada, Yuichi Oike, Makoto Araie, Hitoshi Niwa, Hajime Kubo, Toshio Suda, Kohei Miyazono

Affiliation

¹ Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.

Abstract

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 alpha9 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 alpha9 and VEGF receptor 3 (VEGFR3). In mouse embryos, expression of VEGFR3 and integrin alpha9 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 alpha9 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 alpha9 may function as a key regulator of lymphangiogenesis acting downstream of Prox1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / physiology*
Cell Line
Cell Movement
Chemotaxis
Embryonic Stem Cells
Endothelial Cells / metabolism
Endothelium, Vascular / cytology
Endothelium, Vascular / embryology
Endothelium, Vascular / metabolism
Gene Expression Regulation, Developmental
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism*
Humans
Integrin alpha Chains / genetics
Integrin alpha Chains / metabolism*
Lymphatic System / cytology*
Lymphatic System / embryology
Mice
Prospero-Related Homeobox 1 Protein
Signal Transduction
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*
Vascular Endothelial Growth Factor A / genetics
Vascular Endothelial Growth Factor A / metabolism
Vascular Endothelial Growth Factor C / genetics
Vascular Endothelial Growth Factor C / metabolism
Vascular Endothelial Growth Factor Receptor-3 / genetics
Vascular Endothelial Growth Factor Receptor-3 / metabolism

Substances

Homeodomain Proteins
Integrin alpha Chains
Tumor Suppressor Proteins
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor C
integrin alpha9
Prospero-Related Homeobox 1 Protein
Vascular Endothelial Growth Factor Receptor-3