Multicellular living organisms and unmodified parts thereof and – Nonhuman animal – Transgenic nonhuman animal
Reexamination Certificate
1999-10-26
2002-11-26
Crouch, Deborah (Department: 1632)
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
Transgenic nonhuman animal
C800S003000, C800S021000, C800S022000, C800S025000, C800S018000, C435S455000, C435S463000, C435S320100, C435S325000
Reexamination Certificate
active
06486381
ABSTRACT:
BACKGROUND OF THE INVENTION
1. 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.
2. 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, Fl. (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); Giguère 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
17:427433 (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&agr;, &bgr; and &ggr; and their isoforms) are activated by both all-trans and 9-cis RA, whereas the retinoid X receptor family (RXR&agr;, &bgr; and &ggr;) are activated exclusively by 9-cis RA (for review and refs see 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
17:427433 (1992); Kastner et al., “The role of nuclear retinoic acid receptors in the regulation of gene expression,” in
Vitamin A in health and disease
, R. Blomhoff, ed., Marcel Dekker, New York (1993); Allenby et al.,
Proc. Natl. Acad. Sci. USA
90:30-34 (1993)). Within a given species, the DNA binding (region C) and the ligand binding (region E) domains of the three RAR types are highly similar, whereas the C-terminal region F and the middle region D exhibit no or little similarity. The amino acid sequences of the three RAR types are also notably different in their B regions, and their main isoforms (&agr;1 and &agr;2, &bgr;1 to &bgr;4, and &ggr;1 and &ggr;2) further differ in their N-terminal A regions (reviewed in Leid et al.,
TIBS
17:427-433 (1992)). Similarly, the RXRs characterized to date also markedly differ in their N-terminal A/B regions (Leid et al.,
TIBS
17:427-433 (1992); Leid et al.,
Cell
68:377-395 (1992); Mangelsdorf et al.,
Genes and Dev.
6:329-344 (1992)). Amino acid sequence comparisons revealed that the interspecies conservation of a given RAR or RXR type is greater than the similarity found between the three RAR or RXR types within a given species (reviewed in Leid et al.,
TIBS
17:427433 (1992)). This interspecies conservation is particularly striking in the N-terminal A regions of the various RAR&agr;, &bgr; and &ggr; isoforms, whose A region amino acid sequences are very divergent from each other. Taken together with the distinct spatio-temporal expression patterns observed for the transcripts of each RAR and RXR type in the developing embryo and various adult mouse tissues (Zelent, A., et al.,
Nature
339:714-717 (1989); Dollé et al.,
Nature
342:702-705 (1989); Dollé et al., Development 110:1133-1151 (1990); Ruberte et al.,
Development
108:213-222 (1990); Ruberte et al.,
Development
111:45-60 (1991); Mangelsdorf et al.,
Genes and Dev.
6:329-344 (1992)) this interspecies conservation has suggested that each RAR and RXR type (and isoform) may perform unique functions. This hypothesis is further supported by the finding that the various RAR isoforms and RXR types contain two transcriptional activation functions (AFs) located in the N-terminal A/B region (AF-1) and in the C-terminal E region (AF-2), which can synergistically, and to some extent differentially, activate various RA-responsive promoters (Leid et al.,
TIBS
17:427-433 (1992); Nagpal et al.,
Cell
70:1007-1019 (1992); Nagpal et al.,
EMBO J.
, in press (1993)). Moreover, it has been shown that activation of RA-responsive promoters likely occurs through RAR:RXR heterodimers rather than through homodimers (Yu, V. C. et al.,
Cell
67:1251-1266 (1991); Leid et al.,
Cell
68:377-395 (1992b); Durand et al.,
Cell
71:73-85 (1992); Nagpal et al.,
Cell
70:1007-1019 (1992); Zhang, X. K., et al.,
Nature
355, 441-446 (1992); Kliewer et al.,
Nature
355:446-449 (1992); Bugge et al.,
EMBO J.
11:1409-1418 (1992); Marks et al.,
EMBO J.
11:1419-1435 (1992); for reviews see Yu, V. C. et al.,
Cur. Op. Biotech.
3:597-602 (1992); Leid et al.,
TIBS
17:427-433 (1992); Laudet and Stehelin,
Curr. Biol.
2:293-295 (1992); Green, S.,
Nature
361:590-591 (1993)). Thus, the basis for the highly pleiotropic effect of retinoids may reside, at least in part, through the control of different subsets of retinoid-responsive promoters by cell-specifically expressed heterodimeric combinations of RAR:RXR types (and isoforms), whose activity may be regulated by cell-specific levels of all-trans and 9-cis RA (Leid et
Chambon Pierre
Dierich Andree
Gorry Philippe
Kastner Philippe
Lemeur Marianne
Crouch Deborah
Institut National de la Sante et de la Recherche Medicale
Sterne Kessler Goldstein & Fox P.L.L.C.
Ton Thai-an N.
LandOfFree
Genetically engineered mice containing alterations in the... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Genetically engineered mice containing alterations in the..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Genetically engineered mice containing alterations in the... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2922108