ROLE OF THE MHC IN EARLY MAMMALIAN DEVELOPMENT

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The role of the major histocompatibility complex (MHC) in early mammalian development will be investigated. A key factor in preimplantation embryonic development is the timing of the early cleavage divisions. We have recently discovered a gene, Ped (Preimplantation embryo development), associated with the H-2 complex, which influences the time of the first cleavage division and the subsequent rate of mouse embryonic development. Analysis of congenic strains has shown that embryos of certain haplotypes (k and r) exhibit a slow rate of development, whereas embryos of other haplotypes (b,d,q,a,s,u) develop at a fast rate. Further genetic analysis of Ped gene expression is proposed. First, linkage of the H-2 associated Ped gene to the H-2 complex will be tested by analysis of backcross embryos. Next, it will be determined whether the Ped gene affects the time of implantation or length of gestation. These data are important because there may be Ped genes in humans, associated with the HLA complex, that influence the timing of human development. Another important aspect of early embryonic development is the structure and function of cell surface proteins found on embryos. One class of cell surface molecules, the H-2 antigens, have been shown to be crucially important to a variety of cell-cell interactions between adult cells. However, the detection of H-2 antigens on early mouse embryos has been difficult and controversial. Using a highly sensitive cytotoxicity technique developed in our laboratory, we have been able to show the presence of H-2 antigens on embryos of the k, b, and d haplotypes. Further analysis of the types of H-2 antigens expressed on mouse embryos is proposed. Both conventional antisera and monoclonal antibodies will be used, and positive results will be confirmed by blocking studies with purified H-2 antigens. Finally, the question of whether H-2 antigens on mouse embryos are biologically functional will be probed by attempting to kill mouse embryos with cytotoxic T lymphocytes (CTL's). Since CTL's must recognize H-2 antigens in order to kill their targets, killing of the embryos by CTL's will be excellent evidence that H-2 antigens on mouse embryos are not only serologically detectable, but biologically functional, as well.