SELECTIVE LOSS OF MOUSE EMBRYOS DUE TO THE EXPRESSION OF TRANSGENIC MAJOR HISTOCOMPATIBILITY CLASS-I MOLECULES EARLY IN EMBRYOGENESIS

Among the numerous hypotheses proposed to explain the absence of fetal rejection by the mother in mammals, it has been suggested that regula tion of expression of the polymorphic major histocompatibility complex (MHC) at the fetal-maternal interface plays a major role. In addition to a lack of MHC gene expression in the placenta throughout gestation , the absence of polymorphic MHC molecules on the early embryo, as wel l as their low level of expression after midgestation, could contribut e to this important biologic phenomenon. In order to test this hypothe sis, we have produced transgenic mice able to express polymorphic MHC class I molecules early in embryogenesis. We have placed the MHC class la gene H-2K(b) under the control of a housekeeping gene promoter, th e hydroxy-methyl-glutaryl coenzyme A reductase (HMG) gene minimal prom oter. This construct has been tested for functionality after transfect ion into mouse fibroblast L cells. The analysis of three founder trans genic mice and their progeny suggested that fetoplacental units that c ould express the H-2K(b) heavy chains are unable to survive in utero b eyond midgestation. We have shown further that a much higher resorptio n rate, on days 11 to 13 of embryonic development, is observed among t ransgenic embryos developing from eggs microinjected at the one-cell s tage with the pHMG-K-b construct than in control embryos. This lethali ty is not due to immune phenomena, since it is observed in histocompat ible combinations between mother and fetus. These results are discusse d in the context of what is currently known about the regulation of MH C expression at the fetal-maternal interface and in various transgenic mouse models. (C) 1998 Wiley-Liss, Inc.