Abstract
We have generated transgenic mice carrying human ornithine decarboxylase gene. Two different transgene constructs were used: (i) a 5'-truncated human ornithine decarboxylase gene and (ii) an intact human ornithine decarboxylase gene. Transgenic mice carrying the 5'-truncated gene did not express human ornithine decarboxylase-specific mRNA. Transgenic mice carrying the intact human ornithine decarboxylase gene expressed human-specific ornithine decarboxylase mRNA in all tissues studied. However, as indicated by actual enzyme assays, the expression pattern was highly unusual. In comparison with their wild-type littermates, the transgenic mice exhibited greatly elevated enzyme activity in almost every tissue studied. Ornithine decarboxylase activity was moderately elevated in parenchymal organs such as liver, kidney, and spleen. Tissues like heart, muscle, lung, thymus, testis, and brain displayed an enzyme activity that was 20 to 80 times higher than that in the respective tissues of nontransgenic animals. The offspring of the first transgenic male founder animal did not show any overt abnormalities, yet their reproductive performance was reduced. The second transgenic founder animal, showing similar aberrant expression of ornithine decarboxylase in all tissues studied, including an extremely high activity in testis, was found to be infertile. Histological examination of the tissues of the latter animal revealed marked changes in testicular morphology. The germinal epithelium was hypoplastic, and the spermatogenesis was virtually totally shut off. Similar examination of male members of the first transgenic mouse line revealed comparable, yet less severe, histological changes in testis.
Highlights
We have generated transgenicmice carrying human sion occurs, post-transcriptionally, buteven at some ornithine decarboxylase gene
Gene Constructs Used-The human ornithine decarboxylase gene constructs used for microinjections are shown in Fig. 1.The ornithine decarboxylase genewas originally isolated from human myeloma (Sultan) cells overproducing ornithine decarboxylase owing to gene amplification [16]
As almost 100 pups were born from the microinjected zygotes without a single human ornithine decarboxylase-positive animal, we thought that anactive human ornithine decarboxylase genemay not be compatible with mouse embryogenesis
Summary
Transgenic mice carrying ible (the term is used without any mechanistic implications) the 5“truncatedgene did not express human ornithine mammalian enzymes [1]. Transgenic mice carrying the intacthuman ornithine decarboxylase gene expressed human-specific ornithindeecarboxylase mRNA in all tissues studied. As indicated by actual enzyme assays, theexpression pattern was highly unusual In comparison with their wild-type littermates, the transgenicmice exhibited greatly elevated enzyme activity in almost every tissue studied. The offspringof the first trans-transgenic mice carrying the human ornithine decarboxylase genic male founderanimal did not show any overt gene. Ing similaraberrant expression of ornithine decarbox- The increased enzyme activity was in all likelihood a result ylase in atlilssues studied, including an extremely high of the expression of human ornithine decarboxylase as huactivity in testis, wasfound to be infertile. Similar examination of male members of the first transgenicmouse man-specific mRNA for ornithine decarboxylase was found in all tissues studied. Line revealed comparable, yet less severe, histological changes in testis
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