Ephrin-B2 reverse signaling is required for axon pathfinding and cardiac valve formation but not early vascular development
Ephrin-B2 reverse signaling is required for axon pathfinding and cardiac valve formation but not early vascular development
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DOI：
10.1016/j.ydbio.2004.03.026
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发表时间：
2004-07-15
影响因子：
2.7
通讯作者：
Henkemeyer, M
中科院分区：
文献类型：
--
作者：
Cowan, CA;Yokoyama, N;Henkemeyer, M
血管发育开始于初级血管丛的形成，其通过血管生成迅速重塑为成熟血管系统特征性的互连分支模式。几种受体酪氨酸激酶和它们的配体已经被牵涉到控制血管系统的早期发育。这些包括结合VEGF的血管内皮生长因子受体（VEGFR-1和VEGFR-2）、结合血管生成素的Tie-1和Tie-2受体以及结合膜锚定配体肝配蛋白-B2的EphB 4受体。小鼠生殖系中的靶向突变揭示了这些分子在血管发育中的重要功能。特别地，已经显示从小鼠中删除EphB 4或肝配蛋白-B2的蛋白质无效突变由于血管生成重塑失败而导致早期胚胎死亡。EphB 4的静脉表达和肝配蛋白-B2的动脉表达已经导致推测，这两种分子的相互作用导致双向信号传导进入受体表达细胞和配体表达细胞，并且正向和反向信号都是胚胎中血管正常发育所需的。事实上，另一组靶向去除肝配蛋白-B2羧基末端胞质尾显示扰乱血管发育并导致与无效突变相同的早期胚胎致死性，导致作者提出肝配蛋白-B2反向信号传导指导初级血管丛的早期血管生成重塑[Cell 104（2001）57]。然而，我们在这里表明，肝配蛋白-B2的羧基末端胞质结构域，因此反向信号，是不需要在早期血管发育，但它是必要的新生儿的生存和功能，后来在心血管发育中的成熟的心脏瓣膜小叶。我们进一步表明，肝配蛋白-B2的反向信号是必要的轴突，形成前连合后道的寻路。因此，我们的研究结果表明，ephrin-B2功能在早期胚胎作为一个典型的指导性配体，刺激EphB 4受体的正向信号在血管生成重塑和胚胎发育后期ephrin-B2功能作为受体，以阻止逆转信号参与心脏瓣膜成熟和轴突寻路。(C)2004年爱思唯尔公司All rights reserved.
Vascular development begins with the formation of a primary vascular plexus that is rapidly remodeled by angiogenesis into the interconnected branched patterns characteristic of mature vasculature. Several receptor tyrosine kinases and their ligands have been implicated to control early development of the vascular system. These include the vascular endothelial growth factor receptors (VEGFR-1 and VEGFR-2) that bind VEGF, the Tie-1 and Tie-2 receptors that bind the angiopoietins, and the EphB4 receptor that binds the membrane-anchored ligand ephrin-B2. Targeted mutations in the mouse germline have revealed essential functions for these molecules in vascular development. In particular, protein-null mutations that delete either EphB4 or ephrin-B2 from the mouse have been shown to result in early embryonic lethality due to failed angiogenic remodeling. The venous expression of EphB4 and arterial expression of ephrin-B2 has lead to the speculation that the interaction of these two molecules leads to bidirectional signaling into both the receptor-expressing cell and the ligand-expressing cell, and that both forward and reverse signals are required for proper development of blood vessels in the embryo. Indeed, targeted removal of the ephrin-B2 carboxy-terminal cytoplasmic tail by another group was shown to perturb vascular development and result in the same early embryonic lethality as the null mutation, leading the authors to propose that ephrin-B2 reverse signaling directs early angiogenic remodeling of the primary vascular plexus [Cell 104 (2001) 57]. However, we show here that the carboxy-terminal cytoplasmic domain of ephrin-B2, and hence reverse signaling, is not required during early vascular development, but it is necessary for neonatal survival and functions later in cardiovascular development in the maturation of cardiac valve leaflets. We further show that ephrin-B2 reverse signaling is required for the pathfinding of axons that form the posterior tract of the anterior commissure. Our results thus indicate that ephrin-B2 functions in the early embryo as a typical instructive ligand to stimulate EphB4 receptor forward signaling during angiogenic remodeling and that later in embryonic development ephrin-B2 functions as a receptor to transduce reverse signals involved in cardiac valve maturation and axon pathfinding. (C) 2004 Elsevier Inc. All rights reserved.