Abstract 19542: Endocardial EphB4 Signaling Regulates Neuregulin-1 Expression and is Critically Required for Myocardial Development
The vertebrate ventricular myocardium is formed by a complex and incompletely understood developmental paradigm that regulates accurate organization of an inner trabecular and outer compact zone layers. EphB4, a member of the largest family of receptor tyrosine kinases, is expressed in the developing endocardium, along with its cognate ligand EphrinB2. Whereas EphB4 and EphrinB2 have well-established roles in vascular maturation, their role in cardiac development is unknown. In this study, we show that disruption of embryonic EphB4 expression in the second heart field (Mef2c-cre) or endocardium (Nfat-1c cre) results in a severely thinned and underdeveloped myocardial layer, ventricular non-compaction, heart failure and embryonic lethality around E15.5. Mutant hearts show reduced activation of PI3K pathway and impaired proliferation of developing cardiomyocytes. Knockdown of EphB4 alters multiple downstream signaling pathways of significance in cardiac development. In particular, EphB4 expression regulates neuregulin-1 levels both in vitro and in vivo, which then activates myocardial ErbB receptor signaling. Our study re-iterates the critical role of endocardial signaling in myocardial development. In addition, we identify EphB4 as a novel upstream modulator of Neuregulin-1, and thereby, a critical regulator of myocardial development - a hitherto unrecognized function of this receptor tyrosine kinase.
Author Disclosures: J. Liu: None. B. Ma: None. H. Yen: None. P.S. Gill: None. H.M. Sucov: None. S. Kumar: None.
- © 2014 by American Heart Association, Inc.