Transgenic mice carrying the human beta 2-adrenergic receptor gene with its own promoter overexpress beta 2-adrenergic receptors in liver.
Up to now, transgenic mice models created to study the physiological impact of alterations in the human beta-adrenoceptor system have only focused on cardiac tissues and carried hybrid transgenes with strong cardiac promoters. We have developed a transgenic mouse strain (F28) carrying the human beta 2-adrenoceptor gene with its natural promoter region with the aim of producing a model that more closely reproduces the natural human beta 2-adrenoceptor tissue expression pattern. By means of northern blot analyses, using the appropriate probes, we have obtained evidence that (a) the human beta 2-adrenoceptor's structural gene is transcribed in several tissues of F28 mice; (b) the tissue distribution pattern of human beta 2-adrenoceptor mRNA in F28 mice completely differs from that of mouse beta 2-adrenoceptor mRNA; and (c) the tissue distribution pattern of mouse beta 2-adrenoceptor mRNA in F28 mice is very similar to that observed in their non-transgenic littermates. Like humans, F28 mice express human beta 2-adrenoceptor mRNA in liver, lung, brain, heart, and muscle. However, unlike humans, F28 mice do not accumulate human beta 2-adrenoceptor mRNA in kidney and spleen. By using [125I]iodocyanopindolol to label all beta-adrenoceptors and ICI 118,551 to discriminate between the binding to beta 2- and beta 1-adrenoceptors we have demonstrated that the beta 2-adrenoceptor binding activity increases over control values in F28 mouse tissues that accumulate transgenic mRNA. Accordingly, the number of beta 2-adrenoceptors increased slightly over the control values in muscle, heart, brain, and lung of F28 mice, while in liver these receptors were strongly overexpressed. We further showed that transgene beta 2-adrenoceptors couple to GTP-binding proteins, mediate beta-adrenoceptor agonist-stimulated adenylyl cyclase activation, and cause a strong enhancement of this response in liver membranes of F28 versus control mice. Finally, F28 mice show a phenotype of depressed ponderal development and perturbed hindquarter movements. This unique model should be useful to further investigate beta 2-adrenoceptor causal relationships with human pathologies.
INSERM U380, Institut Cochin de Génétique Moléculaire, Université René Descartes, Paris, France.
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André
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Erraji
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Gaston
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Grimber
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Briand
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JG
Guillet
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D015342:DNA Probes / Q000235:genetics; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D020120:Iodocyanopindolol; D007545:Isoproterenol / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D010641:Phenotype; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000378:metabolism; D014018:Tissue Distribution
D015342:DNA Probes; D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D020120:Iodocyanopindolol; D010869:Pindolol; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol