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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1993 Aug 1;90(15):7225–7229. doi: 10.1073/pnas.90.15.7225

High postnatal lethality and testis degeneration in retinoic acid receptor alpha mutant mice.

T Lufkin 1, D Lohnes 1, M Mark 1, A Dierich 1, P Gorry 1, M P Gaub 1, M LeMeur 1, P Chambon 1
PMCID: PMC47109  PMID: 8394014

Abstract

Retinoic acid (RA) plays a critical role in normal development, growth, and maintenance of certain tissues. The action of RA is thought to be mediated in part by the three nuclear receptors (RAR alpha, -beta, and -gamma), each of which is expressed as multiple isoforms. To investigate the function of the RAR alpha gene, we have disrupted, in the mouse, the whole gene or the isoform RAR alpha 1. Although RAR alpha 1 is the predominant isoform and is highly conserved among vertebrates, RAR alpha 1-null mice appeared normal. However, targeted disruption of the whole RAR alpha gene resulted in early postnatal lethality and testis degeneration. These results, showing that RAR alpha is indeed involved in the transduction of the RA signal, also suggest an unexpected genetic redundancy.

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Selected References

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  1. Brookfield J. Can genes be truly redundant? Curr Biol. 1992 Oct;2(10):553–554. doi: 10.1016/0960-9822(92)90036-a. [DOI] [PubMed] [Google Scholar]
  2. Capecchi M. R. Altering the genome by homologous recombination. Science. 1989 Jun 16;244(4910):1288–1292. doi: 10.1126/science.2660260. [DOI] [PubMed] [Google Scholar]
  3. Chisaka O., Musci T. S., Capecchi M. R. Developmental defects of the ear, cranial nerves and hindbrain resulting from targeted disruption of the mouse homeobox gene Hox-1.6. Nature. 1992 Feb 6;355(6360):516–520. doi: 10.1038/355516a0. [DOI] [PubMed] [Google Scholar]
  4. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  5. Dollé P., Ruberte E., Kastner P., Petkovich M., Stoner C. M., Gudas L. J., Chambon P. Differential expression of genes encoding alpha, beta and gamma retinoic acid receptors and CRABP in the developing limbs of the mouse. Nature. 1989 Dec 7;342(6250):702–705. doi: 10.1038/342702a0. [DOI] [PubMed] [Google Scholar]
  6. Dollé P., Ruberte E., Leroy P., Morriss-Kay G., Chambon P. Retinoic acid receptors and cellular retinoid binding proteins. I. A systematic study of their differential pattern of transcription during mouse organogenesis. Development. 1990 Dec;110(4):1133–1151. doi: 10.1242/dev.110.4.1133. [DOI] [PubMed] [Google Scholar]
  7. Dowling J. E., Wald G. THE BIOLOGICAL FUNCTION OF VITAMIN A ACID. Proc Natl Acad Sci U S A. 1960 May;46(5):587–608. doi: 10.1073/pnas.46.5.587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Durand B., Saunders M., Leroy P., Leid M., Chambon P. All-trans and 9-cis retinoic acid induction of CRABPII transcription is mediated by RAR-RXR heterodimers bound to DR1 and DR2 repeated motifs. Cell. 1992 Oct 2;71(1):73–85. doi: 10.1016/0092-8674(92)90267-g. [DOI] [PubMed] [Google Scholar]
  9. Eskild W., Ree A. H., Levy F. O., Jahnsen T., Hansson V. Cellular localization of mRNAs for retinoic acid receptor-alpha, cellular retinol-binding protein, and cellular retinoic acid-binding protein in rat testis: evidence for germ cell-specific mRNAs. Biol Reprod. 1991 Jan;44(1):53–61. doi: 10.1095/biolreprod44.1.53. [DOI] [PubMed] [Google Scholar]
  10. Gaub M. P., Rochette-Egly C., Lutz Y., Ali S., Matthes H., Scheuer I., Chambon P. Immunodetection of multiple species of retinoic acid receptor alpha: evidence for phosphorylation. Exp Cell Res. 1992 Aug;201(2):335–346. doi: 10.1016/0014-4827(92)90282-d. [DOI] [PubMed] [Google Scholar]
  11. Giguère V., Lyn S., Yip P., Siu C. H., Amin S. Molecular cloning of cDNA encoding a second cellular retinoic acid-binding protein. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6233–6237. doi: 10.1073/pnas.87.16.6233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gossler A., Doetschman T., Korn R., Serfling E., Kemler R. Transgenesis by means of blastocyst-derived embryonic stem cell lines. Proc Natl Acad Sci U S A. 1986 Dec;83(23):9065–9069. doi: 10.1073/pnas.83.23.9065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. HOWELL J. M., THOMPSON J. N., PITT G. A. Histology of the lesions produced in the reproductive tract of animals fed a diet deficient in vitamin A alcohol but containing vitamin A acid. I. The male rat. J Reprod Fertil. 1963 Apr;5:159–167. doi: 10.1530/jrf.0.0050159. [DOI] [PubMed] [Google Scholar]
  14. Ismail N., Morales C., Clermont Y. Role of spermatogonia in the stage-synchronization of the seminiferous epithelium in vitamin-A-deficient rats. Am J Anat. 1990 May;188(1):57–63. doi: 10.1002/aja.1001880107. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Kim K. H., Griswold M. D. The regulation of retinoic acid receptor mRNA levels during spermatogenesis. Mol Endocrinol. 1990 Nov;4(11):1679–1688. doi: 10.1210/mend-4-11-1679. [DOI] [PubMed] [Google Scholar]
  17. Ko M. S. Induction mechanism of a single gene molecule: stochastic or deterministic? Bioessays. 1992 May;14(5):341–346. doi: 10.1002/bies.950140510. [DOI] [PubMed] [Google Scholar]
  18. LaRosa G. J., Gudas L. J. Early retinoic acid-induced F9 teratocarcinoma stem cell gene ERA-1: alternate splicing creates transcripts for a homeobox-containing protein and one lacking the homeobox. Mol Cell Biol. 1988 Sep;8(9):3906–3917. doi: 10.1128/mcb.8.9.3906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lehmann J. M., Zhang X. K., Pfahl M. RAR gamma 2 expression is regulated through a retinoic acid response element embedded in Sp1 sites. Mol Cell Biol. 1992 Jul;12(7):2976–2985. doi: 10.1128/mcb.12.7.2976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Leid M., Kastner P., Chambon P. Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem Sci. 1992 Oct;17(10):427–433. doi: 10.1016/0968-0004(92)90014-z. [DOI] [PubMed] [Google Scholar]
  21. Leroy P., Krust A., Zelent A., Mendelsohn C., Garnier J. M., Kastner P., Dierich A., Chambon P. Multiple isoforms of the mouse retinoic acid receptor alpha are generated by alternative splicing and differential induction by retinoic acid. EMBO J. 1991 Jan;10(1):59–69. doi: 10.1002/j.1460-2075.1991.tb07921.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Leroy P., Nakshatri H., Chambon P. Mouse retinoic acid receptor alpha 2 isoform is transcribed from a promoter that contains a retinoic acid response element. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10138–10142. doi: 10.1073/pnas.88.22.10138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Li E., Sucov H. M., Lee K. F., Evans R. M., Jaenisch R. Normal development and growth of mice carrying a targeted disruption of the alpha 1 retinoic acid receptor gene. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1590–1594. doi: 10.1073/pnas.90.4.1590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Linney E. Retinoic acid receptors: transcription factors modulating gene regulation, development, and differentiation. Curr Top Dev Biol. 1992;27:309–350. doi: 10.1016/s0070-2153(08)60538-4. [DOI] [PubMed] [Google Scholar]
  25. Lufkin T., Dierich A., LeMeur M., Mark M., Chambon P. Disruption of the Hox-1.6 homeobox gene results in defects in a region corresponding to its rostral domain of expression. Cell. 1991 Sep 20;66(6):1105–1119. doi: 10.1016/0092-8674(91)90034-v. [DOI] [PubMed] [Google Scholar]
  26. Mangelsdorf D. J., Borgmeyer U., Heyman R. A., Zhou J. Y., Ong E. S., Oro A. E., Kakizuka A., Evans R. M. Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Genes Dev. 1992 Mar;6(3):329–344. doi: 10.1101/gad.6.3.329. [DOI] [PubMed] [Google Scholar]
  27. Mendelsohn C., Ruberte E., LeMeur M., Morriss-Kay G., Chambon P. Developmental analysis of the retinoic acid-inducible RAR-beta 2 promoter in transgenic animals. Development. 1991 Nov;113(3):723–734. doi: 10.1242/dev.113.3.723. [DOI] [PubMed] [Google Scholar]
  28. Morriss-Kay G. Retinoic acid and craniofacial development: molecules and morphogenesis. Bioessays. 1993 Jan;15(1):9–15. doi: 10.1002/bies.950150103. [DOI] [PubMed] [Google Scholar]
  29. Porter S. B., Ong D. E., Chytil F., Orgebin-Crist M. C. Localization of cellular retinol-binding protein and cellular retinoic acid-binding protein in the rat testis and epididymis. J Androl. 1985 May-Jun;6(3):197–212. doi: 10.1002/j.1939-4640.1985.tb00836.x. [DOI] [PubMed] [Google Scholar]
  30. Rochette-Egly C., Gaub M. P., Lutz Y., Ali S., Scheuer I., Chambon P. Retinoic acid receptor-beta: immunodetection and phosphorylation on tyrosine residues. Mol Endocrinol. 1992 Dec;6(12):2197–2209. doi: 10.1210/mend.6.12.1283441. [DOI] [PubMed] [Google Scholar]
  31. Rochette-Egly C., Lutz Y., Saunders M., Scheuer I., Gaub M. P., Chambon P. Retinoic acid receptor gamma: specific immunodetection and phosphorylation. J Cell Biol. 1991 Oct;115(2):535–545. doi: 10.1083/jcb.115.2.535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ruberte E., Dolle P., Chambon P., Morriss-Kay G. Retinoic acid receptors and cellular retinoid binding proteins. II. Their differential pattern of transcription during early morphogenesis in mouse embryos. Development. 1991 Jan;111(1):45–60. doi: 10.1242/dev.111.1.45. [DOI] [PubMed] [Google Scholar]
  33. Shingleton J. L., Skinner M. K., Ong D. E. Characteristics of retinol accumulation from serum retinol-binding protein by cultured Sertoli cells. Biochemistry. 1989 Dec 12;28(25):9641–9647. doi: 10.1021/bi00451a015. [DOI] [PubMed] [Google Scholar]
  34. Stoner C. M., Gudas L. J. Mouse cellular retinoic acid binding protein: cloning, complementary DNA sequence, and messenger RNA expression during the retinoic acid-induced differentiation of F9 wild type and RA-3-10 mutant teratocarcinoma cells. Cancer Res. 1989 Mar 15;49(6):1497–1504. [PubMed] [Google Scholar]
  35. THOMPSON J. N., HOWELL J. M., PITT G. A. VITAMIN A AND REPRODUCTION IN RATS. Proc R Soc Lond B Biol Sci. 1964 Feb 18;159:510–535. doi: 10.1098/rspb.1964.0017. [DOI] [PubMed] [Google Scholar]
  36. 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]
  37. Tautz D. Redundancies, development and the flow of information. Bioessays. 1992 Apr;14(4):263–266. doi: 10.1002/bies.950140410. [DOI] [PubMed] [Google Scholar]
  38. Thompson J. N., Howell J. M., Pitt G. A., McLaughlin C. I. The biological activity of retinoic acid in the domestic fowl and the effects of vitamin A deficiency on the chick embryo. Br J Nutr. 1969 Aug;23(3):471–490. doi: 10.1079/bjn19690056. [DOI] [PubMed] [Google Scholar]
  39. WILSON J. G., ROTH C. B., WARKANY J. An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation. Am J Anat. 1953 Mar;92(2):189–217. doi: 10.1002/aja.1000920202. [DOI] [PubMed] [Google Scholar]
  40. 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]
  41. van Pelt A. M., de Rooij D. G. Retinoic acid is able to reinitiate spermatogenesis in vitamin A-deficient rats and high replicate doses support the full development of spermatogenic cells. Endocrinology. 1991 Feb;128(2):697–704. doi: 10.1210/endo-128-2-697. [DOI] [PubMed] [Google Scholar]

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