Ephrin Reverse Signaling Controls Palate Fusion Via a PI3 Kinase-Dependent Mechanism

Secondary palate fusion requires adhesion and epithelial-to-mesenchymal transition (EMT) of the epithelial layers on opposing palatal shelves. This EMT requires transforming growth factor beta 3 (TGF beta 3), and its failure results in cleft palate. Ephrins, and their receptors, the Ephs, are responsible for migration, adhesion, and midline closure events throughout development. Ephrins can also act as signal-transducing receptors in these processes, with the Ephs serving as ligands (termed "reverse" signaling). We found that activation of ephrin reverse signaling in chicken palates induced fusion in the absence of TGF beta 3, and that PI3K inhibition abrogated this effect. Further, blockage of reverse signaling inhibited TGF beta 3-induced fusion in the chicken and natural fusion in the mouse. Thus, ephrin reverse signaling is necessary and sufficient to induce palate fusion independent of TGF beta 3. These data describe both a novel role for ephrins in palate morphogenesis, and a previously unknown mechanism of ephrin signaling. Developmental Dynamics 240:357-364, 2011. (C) 2011 Wiley-Liss, Inc.