The Eph family of receptor tyrosine kinases and their membrane-bound ligands, the ephrins, have been implicated in regulating cell adhesion and migration during development by mediating cell-to-cell signaling events. We have shown that ectopic expression of XLerk, a Xenopus homologue of the murine Lerk-2 (ephrin-B1) transmembrane ligand, causes dissociation of Xenopus embryonic blastomeres by the mid-blastula transition. Moreover, a mutant which lacks the extracellular receptor binding domain can induce this phenotype. Basic fibroblast growth factor (bFGF), but not activin, can rescue both the loss of cell adhesion and mesoderm induction in ectodermal explants expressing XLerk. Genetic evidence from other laboratories suggests that ephrins may transduce signals, and become tyrosine phosphorylated during embryogenesis. However, the induction and functional significance of ephrin phosphorylation is not yet clear. Our studies reveal that an activated fibroblast growth factor (FGF) receptor associates with and phosphorylates ephrinB1 on tyrosine. Moreover, this phosphorylation is a regulatory event that alters ephrinB1 function in cell adhesion. In addition, we identify a region in the cytoplasmic tail of ephrinB1 that is critical for direct interaction with the FGF receptor. We also find that FGF treatment of neural tissue expressing ephrinB1 reduces cell binding to a cognate Eph receptor substrate. This is the first demonstration of direct communication between the FGF receptor family and the Eph ligand family and implicates crosstalk between these two cell surface molecules in regulating cell adhesion.My laboratory is also currently studying a novel homeobox protein, Meis 1, that has some homology to the human oncogene product, pbx-1, discovered in human pre- B cell leukemias. The Xenopus homologue of Meis1 (Xmeis1) was isolated and its expression was predominantly found in tissues of neural cell fate, such as midbrain, hindbrain, as well as the neural crest derived branchial arches. Misexpression of Xmeis1b, an alternatively spliced form of Xmeis1a, induced tumor-like accumulations of ectopic pigmented cells in ventral regions of the developing embryo. RT-PCR analysis revealed that Xmeis1b induced ectopic expression of N-tubulin a neuronal marker, Xap2, a neural crest cell marker, and Krox-20, a hindbrain marker encoding a factor that regulates neural crest gene expression. Furthermore, in ectodermal explants, Xmeis1b induced neuronal and neural crest cell markers in the absence of any mesoderm, indicating that Xmeis1b is involved in the neural cell fate specification during embryogenesis.This project has been transferred from BRL to RCGL. - Development, EPH, Receptor Tyrosine Kinase, Xenopus, Homeobox Genes, XMeis,
NIH ExPorter
NIH ExPorter