Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1995-06-27
2000-02-29
Campell, Bruce R.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
435 4, 435 6, 435 71, 435325, 435354, 435375, 435377, 4353201, 435361, 800 18, 800 13, 800 21, 800 22, 800 25, C12N 1500, C12N 1563, C12N 1509, C12N 500
Patent
active
060307943
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to the fields of retinoic acid receptor (RAR) biology and transgenic mice. Specifically, the present invention relates to mice which are deficient in the normal expression of one or more of the genes encoding members of the RAR or RXR class of receptors, to mice heterozygous for such deficiency, to cell lines, preferably pluripotent or totipotent cell lines, which are heterozygous or homozygous for such deficiency, and to methods of using said mice or said cell lines to identify agonists and antagonists of specific members of the RAR or RXR class of receptors.
DESCRIPTION OF THE RELATED ART
It has long been established that retinoids (vitamin A derivatives) are crucial for normal growth, vision, maintenance of numerous tissues, reproduction and overall survival (Wolbach, S. B., and Howe, P. R., J. Exp. Med. 42:753-777 (1925); for reviews and refs see Sporn et al., The retinoids, Vols. 1 and 2, Sporn et al., eds., Academic Press, Orlando, Fla. (1984); Livrea and Packer, in Retinoids, Livrea and Packer, eds., Marcel Dekker, New York (1993)). In addition offspring of vitamin A deficient (VAD) dams exhibit a number of developmental defects, indicating that retinoids are also important during embryogenesis (Wilson, J. G., et al., Am. J. Anat. 92:189-217 (1953)). With the exceptions of vision (Wald, 1968) and possibly of spermatogenesis in mammals (Thompson et al., Proc. Royal Soc. 159:510-535 (1964); van Pelt, H. M. M., and De Rooij, D. G., Endocrinology 128:697-704 (1991); and refs therein), most of the effects generated by VAD in fetuses, young, and adult animals can be prevented and/or reversed by retinoic acid (RA) administration (Wilson, J. G., et al., Am. J. Anat. 92:189-217 (1953); Thompson et al., Proc. Royal Soc. 159:510-535 (1964)). The dramatic teratogenic effects of maternal RA administration on mammalian embryos (Shenefelt, R. E., Teratology 5, 103-108 (1972); Lammer et al., N. Eng. J. Med. 313:837-841 (1985); Webster, W. S. et al., J. Cranofac. Genet. Dev. Biol. 6:211-222 (1986); Kessel and Gruss, Cell 67:89-104 (1991); Kessel, M., Development 115:487-501 (1992); Creech Kraft, J., "Pharmacokinetics, placental transfer, and teratogenicity of 13-cis-retinoic acid, its isomer and metabolites," In Retinoids in Normal Development and Teratogenesis, G. M. Morriss-Kay, ed., Oxford University Press, pp. 267-280 (1992)), and the spectacular effects of topical administration of retinoids on embryonic development of vertebrates and limb regeneration in amphibians (Mohanty-Hejmadi et al., Nature 355:352-353 (1992); for review and refs see Tabin, C. J., Cell 66:199-217 (1991)), has markedly contributed to the belief that RA could in fact be a morphogen (conferring positional information during development), and may also play a critical role during organogenesis.
With the exception of visual perception (Wald, G. et al., Science 162:230-239 (1968)), the molecular mechanisms underlying the highly diverse effects of retinoids has remained obscure until recently. The discovery of nuclear receptors for RA (Petkovich et al., Nature 330:444-450 (1987); Giguere et al., Nature 330:624-629 (1987)) has greatly advanced the understanding of how these simple molecules could exert their pleiotropic effects (for reviews see Leid et al., TIBS 17:427-433 (1992); Linney, E., Current Topics in Dev. Biol. 27:309-350 (1992)). It is thought that the effects of the RA signal are mediated through two families of receptors which belong to the superfamily of ligand-inducible transcriptional regulatory factors that include steroid/thyroid hormone and vitamin D3 receptors (for reviews see Evans, R. M., Science 240:889-895 (1988); Green and Chambon, Trends Genet. 4:309-314 (1988); Beato, M., Cell 56:335-344 (1989); Gronemeyer, H., Ann. Rev. Genet. 25:89-123 (1991); de Luca, L. M., FASEB J. 5:2924-2933 (1991); Linney, E., Current Topics in Dev. Biol. 27:309-350 (1992); Yu, V. C. et al., Cur. Op. Biotech. 3:597-602 (1992); Leid et al., TIBS 17:427-433 (1992)).
The RAR family (RAR.alpha
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Chambon Pierre
Dierich Andree
Gorry Philippe
Kastner Philippe
Lemeur Marianne
Campell Bruce R.
Centre National de la Recherche Scientifique
E. R. Squibb & Sons Inc.
Institut National de la Sante et de la Recherche Medicale
Martin Jill D.
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