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 regulation 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 well as their low level of expression after midgestation, could contribute to this important biologic phenomenon. In order to test this hypothesis, 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-2Kb under the control of a housekeeping gene promoter, the hydroxy-methyl-glutaryl coenzyme A reductase (HMG) gene minimal promoter. This construct has been tested for functionality after transfection into mouse fibroblast L cells. The analysis of three founder transgenic mice and their progeny suggested that fetoplacental units that could express the H-2Kb heavy chains are unable to survive in utero beyond midgestation. We have shown further that a much higher resorption rate, on days 11 to 13 of embryonic development, is observed among transgenic embryos developing from eggs microinjected at the one-cell stage with the pHMG-Kb construct than in control embryos. This lethality is not due to immune phenomena, since it is observed in histocompatible combinations between mother and fetus. These results are discussed in the context of what is currently known about the regulation of MHC expression at the fetal-maternal interface and in various transgenic mouse models.
Aït-Azzouzene
D
D
Department of Developmental Biology, CNRS, Paris, France.
Langkopf
A
A
Cohen
J
J
Bleux
C
C
Gendron
M C
MC
Kanellopoulos-Langevin
C
C
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D020964:Embryo Loss / Q000235:genetics / Q000276:immunology*; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000276:immunology*; D018507:Gene Expression Regulation, Developmental; D006183:H-2 Antigens / Q000235:genetics / Q000502:physiology*; D007739:L Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010063:Ovum; D014162:Transfection
D006183:H-2 Antigens; C032876:H-2Kb protein, mouse