Prox1 Induces Lymphatic Endothelial Differentiation via Integrin α9 and Other Signaling Cascades

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.

Prospero-related homeobox 1 gene (Prox1) is regulated by canonical Wnt signaling and has a stage-specific role in adult hippocampal neurogenesis

“…Thus, the data presented here add an important piece to the transcriptional mechanisms What could be the downstream targets of Prox1 that are important for neuronal differentiation in vitro and in vivo? Several transcriptional targets of Prox1 have been identified, among them a number of genes that could be also important for hippocampal neurogenesis, such as VEGF receptor 3, FGF receptor 3 (35), and α9-integrin (36). Furthermore, a recent study suggested that Prox1 deletion in NSCs and their progeny results in impaired Notch signaling in NSCs, leading to the depletion of the stem cell pool over time (17).…”

Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression

“…This finding suggests that Prox1 is necessary to specify LEC phenotypes in a subset of venous endothelial cells (4). Furthermore, as a homeobox transcription factor, Prox1 is known to upregulate the expression of LEC markers and downregulate BEC markers in mature endothelial cells (5,6). These findings suggest that Prox1 regulates the differentiation program of embryonic BECs to LECs by functioning as a binary transcriptional switch, turning the BEC program off and the LEC program on.…”

Developmental and pathological lymphangiogenesis: from models to human disease

“…In addition, direct PROX1 target genes that mediate its function during the process of lymphangiogenesis are not known. In cultured endothelial cells, PROX1 has been shown to induce the expression of important genes regulating lymphatic development, such as vascular endothelial growth factor receptor-3 (VEGFR-3) Saharinen and Petrova 2004;Wigle et al 2002) and integrin-9 (Mishima et al 2007) thereby promoting the migration of LECs towards the VEGFR-3 ligand, VEGF-C, and regulating the endothelial sheet formation (Mishima et al 2007). PROX1 also regulates the expression of Wbroblast growth factor receptor-3 (FGFR-3) in vitro (Shin et al 2006), however, the role of FGFR-3 in lymphatic vascular development in vivo remains to be investigated.…”