Prox1 induces lymphatic endothelial differentiation via integrin α9 and other signaling cascades
Prox1 induces lymphatic endothelial differentiation via integrin α9 and other signaling cascades
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DOI：
10.1091/mbc.e06-09-0780
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发表时间：
2007-04-01
影响因子：
3.3
通讯作者：
Miyazono, Kohei
中科院分区：
文献类型：
--
作者：
Mishima, Koichi;Watabe, Tetsuro;Miyazono, Kohei
在胚胎淋巴发育过程中，同源盒转录因子Prox1在血管内皮细胞（BECs）亚群向vegf - c表达细胞的发芽和迁移中发挥重要作用。然而，Prox1对内皮细胞行为的影响仍有待阐明。在这里，我们发现Prox1通过诱导整合素α 9的表达，抑制片的形成并刺激内皮细胞的运动。表达prox1的BECs通过上调整合素9和VEGF受体3 （VEGFR3）的表达，优先向VEGF- c迁移。在小鼠胚胎中，与BECs相比，表达prox1的淋巴内皮细胞（LECs）中VEGFR3和整合素9的表达增加。在人LECs中，敲低Prox1的表达导致整合素9和VEGFR3的表达降低，导致对VEGF-C的化学税降低。这些研究结果表明，Prox1通过调节多种信号级联在赋予和维持LECs特征中发挥重要作用，而整合素9可能是Prox1下游淋巴管生成的关键调节剂。
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 alpha 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 a9 and VEGF receptor 3 (VEGFR3). In mouse embryos, expression of VEGFR3 and integrin a9 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 a9 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 a9 may function as a key regulator of lymphangiogenesis acting downstream of Prox1.