Hedgehog induction of murine vasculogenesis is mediated by Foxf1 and Bmp4
Hedgehog induction of murine vasculogenesis is mediated by Foxf1 and Bmp4
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DOI：
10.1242/dev.004432
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发表时间：
2007-10-15
期刊：
影响因子：
4.6
通讯作者：
Carlsson, Peter
中科院分区：
文献类型：
--
作者：
Astorga, Jeanette;Carlsson, Peter
发育中的脊椎动物胚胎的第一个血管系统是由成簇的中胚层血管母细胞将内皮细胞组装成简单的管状结构形成的。血管的成熟涉及到壁细胞的重塑、修剪和包埋。Hedgehog蛋白是指示内胚层信号的一部分，该信号触发中胚层中第一原始血管的组装。我们使用遗传和体外培养相结合的方法来研究刺猬及其靶标在小鼠胚胎外血管形成中的作用。我们发现BMPs，特别是Bmp4对血管形成至关重要，Bmp4在胚外组织中的表达需要叉头转录因子Foxf1，Hedgehog蛋白在这一过程中的作用是激活中胚层中Foxf1的表达。我们在尿囊中发现，Hedgehog信号的遗传干扰(Smo(-/-))对Foxf1的表达没有影响，Bmp4的表达和血管生成都没有受到干扰。相比之下，Foxf1的靶向失活会导致尿囊液Bmp4和血管系统的丧失。在体外，外源性Bmp4可以挽救无血管Foxf1(-/-)表型，BMP拮抗剂noggin可以阻断野生型组织的血管生成。在卵黄囊中，激活Foxf1、Bmp4的表达和血管生成都需要刺猬。然而，Smo(-/-)卵黄囊中的血管生成可以被外源Bmp4拯救，这与Hedgehog信号在初级血管形成中的作用是通过Foxf1激活Bmp4的观点一致。
The first vasculature of the developing vertebrate embryo forms by assembly of endothelial cells into simple tubes from clusters of mesodermal angioblasts. Maturation of this vasculature involves remodeling, pruning and investment with mural cells. Hedgehog proteins are part of the instructive endodermal signal that triggers the assembly of the first primitive vessels in the mesoderm. We used a combination of genetic and in vitro culture methods to investigate the role of hedgehogs and their targets in murine extraembryonic vasculogenesis. We show that Bmps, in particular Bmp4, are crucial for vascular tube formation, that Bmp4 expression in extraembryonic tissues requires the forkhead transcription factor Foxf1 and that the role of hedgehog proteins in this process is to activate Foxf1 expression in the mesoderm. We show in the allantois that genetic disruption of hedgehog signaling ( Smo(-/-)) has no effect on Foxf1 expression, and neither Bmp4 expression nor vasculogenesis are disturbed. By contrast, targeted inactivation of Foxf1 leads to loss of allantoic Bmp4 and vasculature. In vitro, the avascular Foxf1(-/-) phenotype can be rescued by exogenous Bmp4, and vasculogenesis in wild- type tissue can be blocked by the Bmp antagonist noggin. Hedgehogs are required for activation of Foxf1, Bmp4 expression and vasculogenesis in the yolk sac. However, vasculogenesis in Smo(-/-) yolk sacs can be rescued by exogenous Bmp4, consistent with the notion that the role of hedgehog signaling in primary vascular tube formation is as an activator of Bmp4, via Foxf1.