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Nat Commun. 2015 Apr 13;6:6625. doi: 10.1038/ncomms7625.

EphB4 forward signalling regulates lymphatic valve development.

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Department of Molecular Oncology, Division of Research, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Department of Antibody Engineering, Division of Research, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.


Bidirectional signalling is regarded as a notable hallmark of the Eph-ephrin signalling system: Eph-dependent forward signalling in Eph-expressing cells and ephrin-dependent reverse signalling in Ephrin-expressing cells. The notion of ephrin-dependent reverse signalling derives from genetic experiments utilizing mice carrying mutations in the intracellular region of ephrinBs. Here we show that EphB4-dependent forward signalling regulates lymphatic valve development, a process previously thought to be regulated by ephrinB2-dependent reverse signalling. We develop antibodies that selectively target EphB4 and ephrinB2. We find that mice bearing genetically altered cytoplasmic region of ephrinB2 have significantly altered EphB4-dependent forward signalling. Selective inhibition of EphB4 using a functional blocking antibody results in defective lymphatic valve development. Furthermore, a chemical genetic approach is used to unequivocally show that the kinase activity of EphB4 is essential for lymphatic valve development.

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