The close association of maternal reproductive tissues, i.e., the oviduct and uterus, with the developing embryo provides the possibility by which the maternal environment can contribute to early embryonic growth, determination and differentiation. One mechanism through which maternal/fetoplacental signaling can occur is in the exchange of diffusible growth and differentiation factors synthesized by the maternal components for utilization by the embryo. The proto-oncogenes c-kit and c-fms, which encode surface receptors with tyrosine kinase activity, have been shown to be expressed at the mRNA level in the unfertilized oocyte, the pre-implantation embryo and in the embryonic trophectoderm. Both c-kit and c-fms mRNA are also expressed at high levels in the maternal decidual reaction to the implanting blastocyst. Colony-stimulating factor-1 (CSF-1), the ligand for c-fms, has been shown to be expressed at high levels in the endometrial glandular secretory epithelium. Further, CSF-1 mRNA is expressed in the oviduct. Stem cell factor (SCF), the ligand for c-kit, has been shown to be expressed at the mRNA level in the oviduct and the endometrium as well as the placenta. Neither CSF-1 or SCF mRNA are found in the preimplantation embryo. Thus, both c-kit and c-fms represent surface receptors which may participate in a paracrine exchange of signaling from the maternal reproductive tissues to the developing embryo and placenta an well as in the decidual reaction. These ligands and receptors may act alone, in combination or even in a compensatory fashion. The sequential and spatial distribution of c-kit/SCF and c-fms/CSF-1 suggests that these molecules play important roles during early embryonic development, placental maturation and in the decidual response. Existing mouse mutants affecting the expression and/or function of c-kit and c-fms provide a further experimental model for examining these questions. The principal objectives of this proposal will be to investigate the following questions. 1) To determine the temporal and cell-type specific patterns of c-kit and C-fms proto-oncogenes during early embryonic and placental development. 2) To identify trophectoderm specific regulatory upstream genomic sequences controlling the transcription of c-kit and c-fms genes. 3) To determine the level of functional c-kit and c-fms receptors during early embryonic and placental development and what functional role these receptors and their ligands may have in maternal/fetoplacental signaling.
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