Prox1 induces lymphatic endothelial differentiation via integrin alpha9 and other signaling cascades.
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.
Mishima
Koichi
K
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
Watabe
Tetsuro
T
Saito
Akira
A
Yoshimatsu
Yasuhiro
Y
Imaizumi
Natsuko
N
Masui
Shinji
S
Hirashima
Masanori
M
Morisada
Tohru
T
Oike
Yuichi
Y
Araie
Makoto
M
Niwa
Hitoshi
H
Kubo
Hajime
H
Suda
Toshio
T
Miyazono
Kohei
K
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement; D002633:Chemotaxis; D053595:Embryonic Stem Cells; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics / Q000378:metabolism*; D008208:Lymphatic System / Q000166:cytology* / Q000196:embryology; D051379:Mice; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
D018398:Homeodomain Proteins; D039001:Integrin alpha Chains; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; C084613:integrin alpha9; D000098551:Prospero-Related Homeobox 1 Protein; D040321:Vascular Endothelial Growth Factor Receptor-3