EPH Receptors and Ephrins 49

EphB2/EphB3 double knockout mice, and ephrin-B2 knockout mice in at least some genetic backgrounds, also exhibit aberrant sprouting of intersomitic vessels into the adjacent somitic tissue.25 This evidence suggests that forward signaling by EphB3 and EphB4, which are expressed in the mouse intersomitic veins, mediates repulsive signals in response to ephrin-B2 expressed in the posterior portion of the somites and the intersomitic arteries, two structures that flank an ephrin-B2- free path where the intersomitic veins extend.25,71 Consistent with this, widespread expression of ephrin-B2 in the mouse embryo under the control of a ubiquitous promoter, which abolishes discontinuous presentation of endogenous ephrin-B2, causes abnormalities in the projection of intersomitic veins.71 A similar phenotype is caused in Xenopus embryos by ectopic expression of ephrin-B ligands, or overexpression of a dominant negative form of EphB4 that impairs the ability of endogenous endothelial EphB4 to signal.76 Taken together, these data support a model where EphB receptor forward signaling in intersomitic venous endothelial cells inhibits the formation of vascular sprouts extending into ephrin-B territories.

In summary, it appears that a balance of several EphB receptors and ephrin-B ligands expressed in endothelial and vascular support cells is required to achieve proper blood vessel sprouting and remodeling during embryonic development.

5. Lymphatic Vessels

Recent findings have shown that ephrin-B2 and EphB4 are also expressed in lymphatic blood vessels, where they play a critical role in the formation of a functional vascular tree.73 Analysis of LacZ reporter mice revealed that ephrin-B2 is expressed in the endothelial cells of collecting lymphatic vessels, which have smooth muscle cell coverage and contain valves, and EphB4 is widely expressed throughout the lymphatic networks, including capillaries. Interestingly, ephrin-B2 reverse signaling is important in many of the lymphatic vessels. Knockin mice engineered to express a mutated ephrin-B2 lacking the PDZ domain-binding site have accumulation of chylous lymphatic fluid in body cavities and exhibit major lymphatic defects. For example, the