During normal development progenitor cells of many tissues undergo progressive restriction of pluripotency, epithelial-to-mesenchymal transition, proliferation, migration, and differentiation. Most, if not all, of these events involve modifications of cell-cell and cell-matrix adhesion, and abnormal modifications of these adhesion systems are often associated with the formation of tumors. The Eph family of receptor tyrosine kinases and their ligands, the ephrins, are frequently over-expressed in a wide variety of cancers, including breast, small-cell lung and gastrointestinal cancers, melanomas, and neuroblastomas. Using the Xenopus embryonic system, we have demonstrated that signaling mediated by the intracellular domain of ephrinB affects cell-cell adhesion, and that this activity can be modulated by interaction with an activated FGF receptor. We and our collaborators presented evidence that ephrinB1 signaling alters the gastrulation movements of neuro-ectodermal stem cells and is necessary for these cells to move into the eye field. Using loss-of-function (via morpholino oligonucleotides) and gain-of-function or rescue experiments in the amphibian system, we provide critical in vivo evidence that ephrinB1 signaling through its intracellular domain controls retinal progenitor cell movement into the eye field by co-opting the PCP pathway. These findings are unique in several ways. First, we demonstrate that ephrinB1 can associate with Xdsh via the Xdsh DEP domain and mediate the movement of retinal progenitor cells into the eye field. Second, we establish that ephrinB1 control of retinal progenitor movement requires signaling through its intracellular domain and is mediated by downstream members of the non-canonical Wnt/PCP pathway. Moreover, forward signaling through the cognate Eph receptor and canonical Wnt signaling are not essential for this process. We have also found that Signaling through the FGF receptor leads to phosphorylation of ephrinB1 in its C-terminus and de-couples PCP signaling from ephrin. These results importantly bridge two signaling pathways that control cell movement, and two developmental fields, local signaling and stem cell specification. These studies mechanistically link ephrinB1 and the non-canonical Wnt/PCP signaling pathways as co-regulators of an important morphogenetic process, and show that this signaling pathway regulates cell fate by controlling changes in cell movement.
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