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 retinal stem cells and is necessary for these cells to move into the eye field. This year, 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. 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010006-12
Application #
7592616
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2007
Total Cost
$1,200,819
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Lee, Hyun-Shik; Nishanian, Tagvor G; Mood, Kathleen et al. (2008) EphrinB1 controls cell-cell junctions through the Par polarity complex. Nat Cell Biol 10:979-86
Bong, Yong-Sik; Lee, Hyun-Shik; Carim-Todd, Laura et al. (2007) ephrinB1 signals from the cell surface to the nucleus by recruitment of STAT3. Proc Natl Acad Sci U S A 104:17305-10
Lee, Hyun-Shik; Bong, Yong-Sik; Moore, Kathryn B et al. (2006) Dishevelled mediates ephrinB1 signalling in the eye field through the planar cell polarity pathway. Nat Cell Biol 8:55-63
Ishimura, A; Lee, H-S; Bong, Y-S et al. (2006) Oncogenic Met receptor induces ectopic structures in Xenopus embryos. Oncogene 25:4286-99
Mood, Kathleen; Saucier, Caroline; Bong, Yong-Sik et al. (2006) Gab1 is required for cell cycle transition, cell proliferation, and transformation induced by an oncogenic met receptor. Mol Biol Cell 17:3717-28
Mood, Kathleen; Saucier, Caroline; Ishimura, Akihiko et al. (2006) Oncogenic Met receptor induces cell-cycle progression in Xenopus oocytes independent of direct Grb2 and Shc binding or Mos synthesis, but requires phosphatidylinositol 3-kinase and Raf signaling. J Cell Physiol 207:271-85
Murakami, Monica S; Moody, Sally A; Daar, Ira O et al. (2004) Morphogenesis during Xenopus gastrulation requires Wee1-mediated inhibition of cell proliferation. Development 131:571-80
Mood, Kathleen; Bong, Yong-Sik; Lee, Hyun-Shik et al. (2004) Contribution of JNK, Mek, Mos and PI-3K signaling to GVBD in Xenopus oocytes. Cell Signal 16:631-42
Park, Eui Kyun; Warner, Neil; Bong, Yong-Sik et al. (2004) Ectopic EphA4 receptor induces posterior protrusions via FGF signaling in Xenopus embryos. Mol Biol Cell 15:1647-55
Bong, Yong-Sik; Park, Yeon-Hwa; Lee, Hyun-Shik et al. (2004) Tyr-298 in ephrinB1 is critical for an interaction with the Grb4 adaptor protein. Biochem J 377:499-507

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