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. 1992 Mar 15;89(6):2321–2325. doi: 10.1073/pnas.89.6.2321

Multiple retinoid-responsive receptors in a single cell: families of retinoid "X" receptors and retinoic acid receptors in the Xenopus egg.

B Blumberg 1, D J Mangelsdorf 1, J A Dyck 1, D A Bittner 1, R M Evans 1, E M De Robertis 1
PMCID: PMC48649  PMID: 1312717

Abstract

In a search for nuclear hormone receptors expressed in early development we found that Xenopus laevis eggs contain mRNAs from two retinoic acid receptor genes (xRAR alpha and xRAR gamma) and two retinoid "X" receptor genes (xRXR alpha and xRXR gamma). We also show that RXRs are members of a family of at least three genes, thus expanding the number of genes encoding retinoic acid-responsive transcription factors to six. With the exception of xRXR gamma, these maternal mRNAs are degraded before gastrulation. The RXRs isolated are differentially activated by retinoic acid and by 3,4-didehydroretinoic acid. Considered together, these four receptors provide a molecular basis for the pleiotropic effects of retinoic acid on early development, and their pattern of expression suggests a role for retinoic acid at the earliest stages of embryonic determination.

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Selected References

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  1. Auffray C., Rougeon F. Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. Eur J Biochem. 1980 Jun;107(2):303–314. doi: 10.1111/j.1432-1033.1980.tb06030.x. [DOI] [PubMed] [Google Scholar]
  2. Blumberg B., Wright C. V., De Robertis E. M., Cho K. W. Organizer-specific homeobox genes in Xenopus laevis embryos. Science. 1991 Jul 12;253(5016):194–196. doi: 10.1126/science.1677215. [DOI] [PubMed] [Google Scholar]
  3. Brand N., Petkovich M., Krust A., Chambon P., de Thé H., Marchio A., Tiollais P., Dejean A. Identification of a second human retinoic acid receptor. Nature. 1988 Apr 28;332(6167):850–853. doi: 10.1038/332850a0. [DOI] [PubMed] [Google Scholar]
  4. Brockes J. P. Retinoids, homeobox genes, and limb morphogenesis. Neuron. 1989 Apr;2(4):1285–1294. doi: 10.1016/0896-6273(89)90066-4. [DOI] [PubMed] [Google Scholar]
  5. Bürglin T. R., Finney M., Coulson A., Ruvkun G. Caenorhabditis elegans has scores of homoeobox-containing genes. Nature. 1989 Sep 21;341(6239):239–243. doi: 10.1038/341239a0. [DOI] [PubMed] [Google Scholar]
  6. Cho K. W., Blumberg B., Steinbeisser H., De Robertis E. M. Molecular nature of Spemann's organizer: the role of the Xenopus homeobox gene goosecoid. Cell. 1991 Dec 20;67(6):1111–1120. doi: 10.1016/0092-8674(91)90288-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cho K. W., De Robertis E. M. Differential activation of Xenopus homeo box genes by mesoderm-inducing growth factors and retinoic acid. Genes Dev. 1990 Nov;4(11):1910–1916. doi: 10.1101/gad.4.11.1910. [DOI] [PubMed] [Google Scholar]
  8. Cho K. W., Goetz J., Wright C. V., Fritz A., Hardwicke J., De Robertis E. M. Differential utilization of the same reading frame in a Xenopus homeobox gene encodes two related proteins sharing the same DNA-binding specificity. EMBO J. 1988 Jul;7(7):2139–2149. doi: 10.1002/j.1460-2075.1988.tb03053.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Devereux J., Haeberli P., Smithies O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387–395. doi: 10.1093/nar/12.1part1.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Duester G., Shean M. L., McBride M. S., Stewart M. J. Retinoic acid response element in the human alcohol dehydrogenase gene ADH3: implications for regulation of retinoic acid synthesis. Mol Cell Biol. 1991 Mar;11(3):1638–1646. doi: 10.1128/mcb.11.3.1638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Durston A. J., Timmermans J. P., Hage W. J., Hendriks H. F., de Vries N. J., Heideveld M., Nieuwkoop P. D. Retinoic acid causes an anteroposterior transformation in the developing central nervous system. Nature. 1989 Jul 13;340(6229):140–144. doi: 10.1038/340140a0. [DOI] [PubMed] [Google Scholar]
  12. Ellinger-Ziegelbauer H., Dreyer C. A retinoic acid receptor expressed in the early development of Xenopus laevis. Genes Dev. 1991 Jan;5(1):94–104. doi: 10.1101/gad.5.1.94. [DOI] [PubMed] [Google Scholar]
  13. Evans R. M. The steroid and thyroid hormone receptor superfamily. Science. 1988 May 13;240(4854):889–895. doi: 10.1126/science.3283939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Feng D. F., Doolittle R. F. Progressive sequence alignment as a prerequisite to correct phylogenetic trees. J Mol Evol. 1987;25(4):351–360. doi: 10.1007/BF02603120. [DOI] [PubMed] [Google Scholar]
  15. Giguere V., Ong E. S., Segui P., Evans R. M. Identification of a receptor for the morphogen retinoic acid. Nature. 1987 Dec 17;330(6149):624–629. doi: 10.1038/330624a0. [DOI] [PubMed] [Google Scholar]
  16. Giguère V., Shago M., Zirngibl R., Tate P., Rossant J., Varmuza S. Identification of a novel isoform of the retinoic acid receptor gamma expressed in the mouse embryo. Mol Cell Biol. 1990 May;10(5):2335–2340. doi: 10.1128/mcb.10.5.2335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hamada K., Gleason S. L., Levi B. Z., Hirschfeld S., Appella E., Ozato K. H-2RIIBP, a member of the nuclear hormone receptor superfamily that binds to both the regulatory element of major histocompatibility class I genes and the estrogen response element. Proc Natl Acad Sci U S A. 1989 Nov;86(21):8289–8293. doi: 10.1073/pnas.86.21.8289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Heyman R. A., Mangelsdorf D. J., Dyck J. A., Stein R. B., Eichele G., Evans R. M., Thaller C. 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell. 1992 Jan 24;68(2):397–406. doi: 10.1016/0092-8674(92)90479-v. [DOI] [PubMed] [Google Scholar]
  19. Kastner P., Krust A., Mendelsohn C., Garnier J. M., Zelent A., Leroy P., Staub A., Chambon P. Murine isoforms of retinoic acid receptor gamma with specific patterns of expression. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2700–2704. doi: 10.1073/pnas.87.7.2700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kliewer S. A., Umesono K., Heyman R. A., Mangelsdorf D. J., Dyck J. A., Evans R. M. Retinoid X receptor-COUP-TF interactions modulate retinoic acid signaling. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1448–1452. doi: 10.1073/pnas.89.4.1448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Krieg P. A., Melton D. A. Functional messenger RNAs are produced by SP6 in vitro transcription of cloned cDNAs. Nucleic Acids Res. 1984 Sep 25;12(18):7057–7070. doi: 10.1093/nar/12.18.7057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Krieg P. A., Varnum S. M., Wormington W. M., Melton D. A. The mRNA encoding elongation factor 1-alpha (EF-1 alpha) is a major transcript at the midblastula transition in Xenopus. Dev Biol. 1989 May;133(1):93–100. doi: 10.1016/0012-1606(89)90300-x. [DOI] [PubMed] [Google Scholar]
  23. Krust A., Kastner P., Petkovich M., Zelent A., Chambon P. A third human retinoic acid receptor, hRAR-gamma. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5310–5314. doi: 10.1073/pnas.86.14.5310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lammer E. J., Chen D. T., Hoar R. M., Agnish N. D., Benke P. J., Braun J. T., Curry C. J., Fernhoff P. M., Grix A. W., Jr, Lott I. T. Retinoic acid embryopathy. N Engl J Med. 1985 Oct 3;313(14):837–841. doi: 10.1056/NEJM198510033131401. [DOI] [PubMed] [Google Scholar]
  25. Levin A. A., Sturzenbecker L. J., Kazmer S., Bosakowski T., Huselton C., Allenby G., Speck J., Kratzeisen C., Rosenberger M., Lovey A. 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha. Nature. 1992 Jan 23;355(6358):359–361. doi: 10.1038/355359a0. [DOI] [PubMed] [Google Scholar]
  26. Mangelsdorf D. J., Ong E. S., Dyck J. A., Evans R. M. Nuclear receptor that identifies a novel retinoic acid response pathway. Nature. 1990 May 17;345(6272):224–229. doi: 10.1038/345224a0. [DOI] [PubMed] [Google Scholar]
  27. Mangelsdorf D. J., Umesono K., Kliewer S. A., Borgmeyer U., Ong E. S., Evans R. M. A direct repeat in the cellular retinol-binding protein type II gene confers differential regulation by RXR and RAR. Cell. 1991 Aug 9;66(3):555–561. doi: 10.1016/0092-8674(81)90018-0. [DOI] [PubMed] [Google Scholar]
  28. Oro A. E., McKeown M., Evans R. M. Relationship between the product of the Drosophila ultraspiracle locus and the vertebrate retinoid X receptor. Nature. 1990 Sep 20;347(6290):298–301. doi: 10.1038/347298a0. [DOI] [PubMed] [Google Scholar]
  29. Petkovich M., Brand N. J., Krust A., Chambon P. A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature. 1987 Dec 3;330(6147):444–450. doi: 10.1038/330444a0. [DOI] [PubMed] [Google Scholar]
  30. Rowe A., Eager N. S., Brickell P. M. A member of the RXR nuclear receptor family is expressed in neural-crest-derived cells of the developing chick peripheral nervous system. Development. 1991 Mar;111(3):771–778. doi: 10.1242/dev.111.3.771. [DOI] [PubMed] [Google Scholar]
  31. Ruiz i Altaba A., Jessell T. Retinoic acid modifies mesodermal patterning in early Xenopus embryos. Genes Dev. 1991 Feb;5(2):175–187. doi: 10.1101/gad.5.2.175. [DOI] [PubMed] [Google Scholar]
  32. Ruiz i Altaba A., Melton D. A. Interaction between peptide growth factors and homoeobox genes in the establishment of antero-posterior polarity in frog embryos. Nature. 1989 Sep 7;341(6237):33–38. doi: 10.1038/341033a0. [DOI] [PubMed] [Google Scholar]
  33. Short J. M., Fernandez J. M., Sorge J. A., Huse W. D. Lambda ZAP: a bacteriophage lambda expression vector with in vivo excision properties. Nucleic Acids Res. 1988 Aug 11;16(15):7583–7600. doi: 10.1093/nar/16.15.7583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sive H. L., Cheng P. F. Retinoic acid perturbs the expression of Xhox.lab genes and alters mesodermal determination in Xenopus laevis. Genes Dev. 1991 Aug;5(8):1321–1332. doi: 10.1101/gad.5.8.1321. [DOI] [PubMed] [Google Scholar]
  35. Sive H. L., Draper B. W., Harland R. M., Weintraub H. Identification of a retinoic acid-sensitive period during primary axis formation in Xenopus laevis. Genes Dev. 1990 Jun;4(6):932–942. doi: 10.1101/gad.4.6.932. [DOI] [PubMed] [Google Scholar]
  36. Staden R. The current status and portability of our sequence handling software. Nucleic Acids Res. 1986 Jan 10;14(1):217–231. doi: 10.1093/nar/14.1.217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sucov H. M., Murakami K. K., Evans R. M. Characterization of an autoregulated response element in the mouse retinoic acid receptor type beta gene. Proc Natl Acad Sci U S A. 1990 Jul;87(14):5392–5396. doi: 10.1073/pnas.87.14.5392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Tabin C. J. Retinoids, homeoboxes, and growth factors: toward molecular models for limb development. Cell. 1991 Jul 26;66(2):199–217. doi: 10.1016/0092-8674(91)90612-3. [DOI] [PubMed] [Google Scholar]
  39. Thaller C., Eichele G. Isolation of 3,4-didehydroretinoic acid, a novel morphogenetic signal in the chick wing bud. Nature. 1990 Jun 28;345(6278):815–819. doi: 10.1038/345815a0. [DOI] [PubMed] [Google Scholar]
  40. Umesono K., Giguere V., Glass C. K., Rosenfeld M. G., Evans R. M. Retinoic acid and thyroid hormone induce gene expression through a common responsive element. Nature. 1988 Nov 17;336(6196):262–265. doi: 10.1038/336262a0. [DOI] [PubMed] [Google Scholar]
  41. Vasios G. W., Gold J. D., Petkovich M., Chambon P., Gudas L. J. A retinoic acid-responsive element is present in the 5' flanking region of the laminin B1 gene. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9099–9103. doi: 10.1073/pnas.86.23.9099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Weeks D. L., Melton D. A. A maternal mRNA localized to the vegetal hemisphere in Xenopus eggs codes for a growth factor related to TGF-beta. Cell. 1987 Dec 4;51(5):861–867. doi: 10.1016/0092-8674(87)90109-7. [DOI] [PubMed] [Google Scholar]
  43. Zelent A., Krust A., Petkovich M., Kastner P., Chambon P. Cloning of murine alpha and beta retinoic acid receptors and a novel receptor gamma predominantly expressed in skin. Nature. 1989 Jun 29;339(6227):714–717. doi: 10.1038/339714a0. [DOI] [PubMed] [Google Scholar]
  44. de Thé H., Vivanco-Ruiz M. M., Tiollais P., Stunnenberg H., Dejean A. Identification of a retinoic acid responsive element in the retinoic acid receptor beta gene. Nature. 1990 Jan 11;343(6254):177–180. doi: 10.1038/343177a0. [DOI] [PubMed] [Google Scholar]

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