Skip to main content
SpringerLink
Log in

Contribution of Targeted Conditional Somatic Mutagenesis to Deciphering Retinoid X Receptor Functions and to Generating Mouse Models of Human Diseases

  • Chapter
Conditional Mutagenesis: An Approach to Disease Models

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 178))

Abstract

The last decade has witnessed an enormous rise in the interest for retinoid signalling and its cognate receptors, because of their central role in the coordination of development and homeostasis, through their ability to orchestrate the expression of numerous target genes. These receptors include six nuclear receptor (NR) family members, the retinoic acid receptor (RAR) α, β and γ, and the retinoid X receptor (RXR) α, β and γ, which are expressed in many cell types in mammals. Analysis of the development of mouse embryos bearing retinoid receptor null mutations demonstrated that these receptors transduce the effects of retinoic acid (RA, the active derivative of vitamin A) in vivo, and revealed impressive complexity. However, frequent redundancy in receptor functions and lethality of compound RAR-null mutants, as well as of RXRα-null mutants, precluded the characterisation of the functions of these receptors during late development and postnatally. We illustrate here how recent developments of conditional targeted somatic mutagenesis have opened new avenues in analysing the physiological functions of retinoid X receptor signalling in a variety of tissues and cell types, as well as in exploring the pathophysiological consequences of their alteration that led to novel mouse models of human diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Aboseif S, Shinohara K, Borirakchanyavat S, Deirmenjian J, Carroll PR (1997) The effect of cryosurgical ablation of the prostate on erectile function. Br J Urol 80:918–922

    PubMed  CAS  Google Scholar 

  • Bok D (1993) The retinal pigment epithelium: a versatile partner in vision. J Cell Sci Suppl 17:189–195

    PubMed  CAS  Google Scholar 

  • Bok D (2002) New insights and new approaches toward the study of age-related macular degeneration. Proc Natl Acad Sci U S A 99:14619–14621

    Article  PubMed  CAS  Google Scholar 

  • Chambon P (1994) The retinoid signaling pathway: molecular and genetic analyses. Semin Cell Biol 5:115–125

    Article  PubMed  CAS  Google Scholar 

  • Chambon P (2005) The nuclear receptor superfamily: a personal retrospect on the first two decades. Mol Endocrinol 19:1418–1428

    Article  PubMed  CAS  Google Scholar 

  • Chen J, Kubalak SW, Chien KR (1998) Ventricular muscle-restricted targeting of the RXRalpha gene reveals a non-cell-autonomous requirement in cardiac chamber morphogenesis. Development 125:1943–1949

    PubMed  CAS  Google Scholar 

  • Chopra DP, Wilkoff LJ (1977) Reversal by vitamin A analogues (retinoids) of hyperplasia induced by N-methyl-N′-nitro-N-nitrosoguanidine in mouse prostate organ cultures. J Natl Cancer Inst 58:923–930

    PubMed  CAS  Google Scholar 

  • Dahiya R, Park H D, Cusick J, Vessella RL, Fournier G, Narayan P (1994) Inhibition of tumorigenic potential and prostate-specific antigen expression in LNCaP human prostate cancer cell line by 13-cis-retinoic acid. Int J Cancer 59:126–132

    PubMed  CAS  Google Scholar 

  • De Vos S, Dawson MI, Holden S, Le T, Wang A, Cho SK, Chen DL, Koeffler HP (1997) Effects of retinoid X receptor-selective ligands on proliferation of prostate cancer cells. Prostate 32:115–121

    Article  PubMed  Google Scholar 

  • Dyson E, Sucov HM, Kubalak SW, Schmid-Schonbein GW, DeLano FA, Evans RM, Ross J, Jr., and Chien KR (1995) Atrial-like phenotype is associated with embryonic ventricular failure in retinoid X receptor alpha-/-mice. Proc Natl Acad Sci U S A 92:7386–7390

    Article  PubMed  CAS  Google Scholar 

  • Evans RM (2005) The nuclear receptor superfamily: a rosetta stone for physiology. Mol Endocrinol 19:1429–1438

    Article  PubMed  CAS  Google Scholar 

  • Fasshauer M, and Paschke R (2003) Regulation of adipocytokines and insulin resistance. Diabetologia 46:1594–1603

    Article  PubMed  CAS  Google Scholar 

  • Fisher GJ, and Voorhees JJ (1996) Molecular mechanisms of retinoid actions in skin. Faseb J 10:1002–1013

    PubMed  CAS  Google Scholar 

  • Fuchs E (1997) Keith RPorter Lecture 1996. Of mice and men: genetic disorders of the cytoskeleton. Mol Biol Cell 8:189–203

    PubMed  CAS  Google Scholar 

  • Grondona JM, Kastner P, Gansmuller A, Decimo D, Chambon P, Mark M (1996) Retinal dysplasia and degeneration in RARbeta2/RARgamma2 compound mutant mice. Development 122:2173–2188

    PubMed  CAS  Google Scholar 

  • Gruber PJ, Kubalak SW, Pexieder T, Sucov HM, Evans RM, Chien KR (1996) RXR alpha deficiency confers genetic susceptibility for aortic sac, conotruncal, atrioventricular cushion, and ventricular muscle defects in mice. J Clin Invest 98:1332–1343

    PubMed  CAS  Google Scholar 

  • Hardy MH (1992) The secret life of the hair follicle. Trends Genet 8:55–61

    PubMed  CAS  Google Scholar 

  • Hsing AW, Comstock GW, Abbey H, Polk BF (1990) Serologic precursors of cancer. Retinol, carotenoids, and tocopherol and risk of prostate cancer. J Natl Cancer Inst 82:941–946

    Article  PubMed  CAS  Google Scholar 

  • Huang J, Powell WC, Khodavirdi AC, Wu J, Makita T, Cardiff RD, Cohen MB, Sucov HM, Roy-Burman P (2002) Prostatic intraepithelial neoplasia in mice with conditional disruption of the retinoid X receptor alpha allele in the prostate epithelium. Cancer Res 62:4812–4819

    PubMed  CAS  Google Scholar 

  • Huang W, Ma K, Zhang J, Qatanani M, Cuvillier J, Liu J, Dong B, Huang X, Moore DD (2006) Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312:233–236

    Article  PubMed  CAS  Google Scholar 

  • Imai T, Jiang M, Chambon P, Metzger D (2001a) Impaired adipogenesis and lipolysis in the mouse upon selective ablation of the retinoid X receptor alpha mediated by a tamoxifen-inducible chimeric Cre recombinase (Cre-ERT2) in adipocytes. Proc Natl Acad Sci U S A 98:224–228

    Article  PubMed  CAS  Google Scholar 

  • Imai T, Jiang M, Kastner P, Chambon P, Metzger D (2001b) Selective ablation of retinoid X receptor alpha in hepatocytes impairs their lifespan and regenerative capacity. Proc Natl Acad Sci U S A 98:4581–4586

    Article  PubMed  CAS  Google Scholar 

  • Imai T, Takakuwa R, Marchand S, Dentz E, Bornert JM, Messaddeq N, Wendling O, Mark M, Desvergne B, Wahli W et al (2004) Peroxisome proliferator-activated receptor gamma is required in mature white and brown adipocytes for their survival in the mouse. Proc Natl Acad Sci U S A 101:4543–4547

    Article  PubMed  CAS  Google Scholar 

  • Kastner P, Grondona JM, Mark M, Gansmuller A, LeMeur M, Decimo D, Vonesch JL, Dolle P, Chambon P (1994) Genetic analysis of RXR alpha developmental function: convergence of RXR and RAR signaling pathways in heart and eye morphogenesis. Cell 78:987–1003

    Article  PubMed  CAS  Google Scholar 

  • Kastner P, Mark M, Chambon P (1995) Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell 83:859–869

    Article  PubMed  CAS  Google Scholar 

  • Kastner P, Mark M, Leid M, Gansmuller A, Chin W, Grondona JM, Decimo D, Krezel W, Dierich A, Chambon P (1996) Abnormal spermatogenesis in RXR beta mutant mice. Genes Dev 10:80–92

    PubMed  CAS  Google Scholar 

  • Krezel W, Dupe V, Mark M, Dierich A, Kastner P, Chambon P (1996) RXR gamma null mice are apparently normal and compound RXR alpha +/−/RXR beta−/−/RXR gamma−/− mutant mice are viable. Proc Natl Acad Sci U S A 93:9010–9014

    PubMed  CAS  Google Scholar 

  • Kubalak SW, Hutson DR, Scott KK, Shannon RA (2002) Elevated transforming growth factor beta2 enhances apoptosis and contributes to abnormal outflow tract and aortic sac development in retinoic X receptor alpha knockout embryos. Development 129:733–746

    PubMed  CAS  Google Scholar 

  • Lasnitzki I, Goodman DS (1974) Inhibition of the effects of methylcholanthrene on mouse prostate in organ culture by vitamin A and its analogs. Cancer Res 34:1564–1571

    PubMed  CAS  Google Scholar 

  • Li M, Indra AK, Warot X, Brocard J, Messaddeq N, Kato S, Metzger D, Chambon P (2000) Skin abnormalities generated by temporally controlled RXRalpha mutations in mouse epidermis. Nature 407:633–636

    Article  PubMed  CAS  Google Scholar 

  • Li M, Chiba H, Warot X, Messaddeq N, Gerard C, Chambon P, Metzger D (2001) RXR-alpha ablation in skin keratinocytes results in alopecia and epidermal alterations. Development 128:675–688

    PubMed  CAS  Google Scholar 

  • Li M, Messaddeq N, Teletin M, Pasquali JL, Metzger D, Chambon P (2005) Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin. Proc Natl Acad Sci U S A 102:14795–14800

    Article  PubMed  CAS  Google Scholar 

  • Li M, Hener P, Zhikun Z, Kato P, Metzger D, Chambon P (2006) Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc Natl Acad Sci U S A 103:11736–11741

    Article  PubMed  CAS  Google Scholar 

  • Lohnes D, Kastner P, Dierich A, Mark M, LeMeur M, Chambon P (1993) Function of retinoic acid receptor gamma in the mouse. Cell 73:643–658

    Article  PubMed  CAS  Google Scholar 

  • Lufkin T, Lohnes D, Mark M, Dierich A, Gorry P, Gaub MP, LeMeur M, Chambon P (1993) High postnatal lethality and testis degeneration in retinoic acid receptor alpha mutant mice. Proc Natl Acad Sci U S A 90:7225–7229

    Article  PubMed  CAS  Google Scholar 

  • Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM (1995) The nuclear receptor superfamily: the second decade. Cell 83:835–839

    Article  PubMed  CAS  Google Scholar 

  • McBee JK, Palczewski K, Baehr W, Pepperberg DR (2001) Confronting complexity: the interlink of phototransduction and retinoid metabolism in the vertebrate retina. Prog Retin Eye Res 20:469–529

    Article  PubMed  CAS  Google Scholar 

  • Mendelsohn C, Mark M, Dolle P, Dierich A, Gaub MP, Krust A, Lampron C, Chambon P (1994) Retinoic acid receptor beta 2 (RAR beta 2) null mutant mice appear normal. Dev Biol 166:246–258

    Article  PubMed  CAS  Google Scholar 

  • Merki E, Zamora M, Raya A, Kawakami Y, Wang J, Zhang X, Burch J, Kubalak SW, Kaliman P, Belmonte JC et al (2005) Epicardial retinoid X receptor alpha is required for myocardial growth and coronary artery formation. Proc Natl Acad Sci U S A 102:18455–18460

    Article  PubMed  CAS  Google Scholar 

  • Mori M, Metzger D, Picaud S, Hindelang C, Simonutti M, Sahel J, Chambon P, Mark M (2004) Retinal dystrophy resulting from ablation of RXR alpha in the mouse retinal pigment epithelium. Am J Pathol 164:701–710

    PubMed  CAS  Google Scholar 

  • Nguyen-Legros J, Hicks D (2000) Renewal of photoreceptor outer segments and their phagocytosis by the retinal pigment epithelium. Int Rev Cytol 196:245–313

    PubMed  CAS  Google Scholar 

  • Paus R, Cotsarelis G (1999) The biology of hair follicles. N Engl J Med 341:491–497

    Article  PubMed  CAS  Google Scholar 

  • Pollard M, Luckert PH, Sporn MB (1991) Prevention of primary prostate cancer in Lobund-Wistar rats by N-(4-hydroxyphenyl)retinamide. Cancer Res 51:3610–3611

    PubMed  CAS  Google Scholar 

  • Reichman ME, Hayes RB, Ziegler RG, Schatzkin A, Taylor PR, Kahle LL, Fraumeni JF Jr (1990) Serum vitamin A and subsequent development of prostate cancer in the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. Cancer Res 50:2311–2315

    PubMed  CAS  Google Scholar 

  • Roy-Burman P, Wu H, Powell WC, Hagenkord J, Cohen MB (2004) Genetically defined mouse models that mimic natural aspects of human prostate cancer development. Endocr Relat Cancer 11:225–254

    Article  PubMed  CAS  Google Scholar 

  • Saari JC (2000) Biochemistry of visual pigment regeneration: the Friedenwald lecture. Invest Ophthalmol Vis Sci 41:337–348

    PubMed  CAS  Google Scholar 

  • Seo R, McGuire M, Chung M, Bushman W (1997) Inhibition of prostate ductal morphogenesis by retinoic acid. J Urol 158:931–935

    Article  PubMed  CAS  Google Scholar 

  • Subbarayan V, Mark M, Messadeq N, Rustin P, Chambon P, and Kastner P (2000) RXRalpha overexpression in cardiomyocytes causes dilated cardiomyopathy but fails to rescue myocardial hypoplasia in RXRalpha-null fetuses. J Clin Invest 105:387–394

    PubMed  CAS  Google Scholar 

  • Sucov HM, Dyson E, Gumeringer CL, Price J, Chien KR, Evans RM (1994) RXR alpha mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis. Genes Dev 8:1007–1018

    PubMed  CAS  Google Scholar 

  • Tontonoz P, Hu E, Spiegelman BM (1994) Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 79:1147–1156

    Article  PubMed  CAS  Google Scholar 

  • Tran CM, Sucov HM (1998) The RXRalpha gene functions in a non-cell-autonomous manner during mouse cardiac morphogenesis. Development 125:1951–1956

    PubMed  CAS  Google Scholar 

  • Wan YJ, An D, Cai Y, Repa JJ, Hung-Po Chen T, Flores M, Postic C, Magnuson MA, Chen J, Chien KR et al (2000a) Hepatocyte-specific mutation establishes retinoid X receptor alpha as a heterodimeric integrator of multiple physiological processes in the liver. Mol Cell Biol 20:4436–4444

    Article  PubMed  CAS  Google Scholar 

  • Wan YJ, Cai Y, Lungo W, Fu P, Locker J, French S, Sucov HM (2000b) Peroxisome proliferator-activated receptor alpha-mediated pathways are altered in hepatocyte-specific retinoid X receptor alpha-deficient mice. J Biol Chem 275:28285–28290

    PubMed  CAS  Google Scholar 

  • Wilson JG, Roth CB, Warkany J (1953) 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 92:189–217

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, BP10142, 67404, Illkirch Cedex, France

    D. Metzger & P. Chambon

Authors
  1. D. Metzger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Chambon
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Interfakultäres Institut für Biochemie (IFIB) Signaltransduktion — transgene Modelle, Universität Tübingen, Hoppe-Seyler-Str. 4, 72076, Tübingen, Germany

    Robert Feil

  2. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, 67404, Illkirch, France

    Daniel Metzger

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Metzger, D., Chambon, P. (2007). Contribution of Targeted Conditional Somatic Mutagenesis to Deciphering Retinoid X Receptor Functions and to Generating Mouse Models of Human Diseases. In: Feil, R., Metzger, D. (eds) Conditional Mutagenesis: An Approach to Disease Models. Handbook of Experimental Pharmacology, vol 178. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-35109-2_21

Download citation

Publish with us

Policies and ethics

Search

Navigation