RXR-alpha ablation in skin keratinocytes results in alopecia and epidermal alterations.

RXR-alpha is the most abundant of the three retinoid X receptors (RXRs) in the epidermis. In this study, we have used Cre-mediated recombination to selectively disrupt the mouse gene for RXR-alpha in epidermal and hair follicle keratinocytes. We show that RXR-alpha is apparently dispensable for prenatal epidermal development, while it is involved in postnatal skin maturation. After the first hair pelage, mutant mice develop a progressive alopecia, histologically characterised by the destruction of hair follicle architecture and the formation of utriculi and dermal cysts in adult mice. Our results demonstrate that RXR-alpha plays a key role in anagen initiation during the hair follicle cycle. In addition, RXR-alpha ablation results in epidermal interfollicular hyperplasia with keratinocyte hyperproliferation and aberrant terminal differentiation, accompanied by an inflammatory reaction of the skin. Our data not only provide genetic evidence that RXR-alpha/VDR heterodimers play a major role in controlling hair cycling, but also suggest that additional signalling pathways mediated by RXR-alpha heterodimerised with other nuclear receptors are involved in postnatal hair follicle growth, and homeostasis of proliferation/differentiation of epidermal keratinocytes and of the skin's immune system.

[1]  P. Chambon,et al.  Skin abnormalities generated by temporally controlled RXRα mutations in mouse epidermis , 2000, Nature.

[2]  J. Ward,et al.  Growth, Adipose, Brain, and Skin Alterations Resulting from Targeted Disruption of the Mouse Peroxisome Proliferator-Activated Receptor β(δ) , 2000, Molecular and Cellular Biology.

[3]  Mark A. Magnuson,et al.  Hepatocyte-Specific Mutation Establishes Retinoid X Receptor α as a Heterodimeric Integrator of Multiple Physiological Processes in the Liver , 2000, Molecular and Cellular Biology.

[4]  M. Demay,et al.  Evaluation of keratinocyte proliferation and differentiation in vitamin D receptor knockout mice. , 2000, Endocrinology.

[5]  J. Auwerx,et al.  Farnesol Stimulates Differentiation in Epidermal Keratinocytes via PPARα* , 2000, The Journal of Biological Chemistry.

[6]  B. Bernard,et al.  Thyroid hormone receptor β1 is expressed in the human hair follicle , 2000 .

[7]  D. Mangelsdorf,et al.  Oxysterols induce differentiation in human keratinocytes and increase Ap-1-dependent involucrin transcription. , 2000, The Journal of investigative dermatology.

[8]  A. Enk,et al.  Epidermal overexpression of granulocyte-macrophage colony-stimulating factor induces both keratinocyte proliferation and apoptosis. , 2000, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[9]  Andras Nagy,et al.  Cre recombinase: The universal reagent for genome tailoring , 2000, Genesis.

[10]  P Chambon,et al.  Temporally-controlled site-specific mutagenesis in the basal layer of the epidermis: comparison of the recombinase activity of the tamoxifen-inducible Cre-ER(T) and Cre-ER(T2) recombinases. , 1999, Nucleic acids research.

[11]  R Paus,et al.  The biology of hair follicles. , 1999, The New England journal of medicine.

[12]  E. Fuchs,et al.  The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[13]  J. Pike,et al.  The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets. , 1999, Endocrine reviews.

[14]  P. Chambon,et al.  Identification of heparin‐binding EGF‐like growth factor as a target in intercellular regulation of epidermal basal cell growth by suprabasal retinoic acid receptors , 1999, The EMBO journal.

[15]  P. Chambon,et al.  Retinoid X receptors are essential for early mouse development and placentogenesis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[16]  P. Chambon,et al.  The RXRalpha ligand-dependent activation function 2 (AF-2) is important for mouse development. , 1998, Development.

[17]  M. Scott,et al.  Splitting Hairs Dissecting Roles of Signaling Systems in Epidermal Development , 1998, Cell.

[18]  J. Sundberg,et al.  Molecular and functional aspects of the hairless (hr) gene in laboratory rodents and humans , 1998, Experimental dermatology.

[19]  P. Elias,et al.  Ligands and activators of nuclear hormone receptors regulate epidermal differentiation during fetal rat skin development. , 1998, The Journal of investigative dermatology.

[20]  D. Bickers,et al.  Retinoid metabolism in the skin. , 1998, Pharmacological reviews.

[21]  E. Lane,et al.  The relationship between hyperproliferation and epidermal thickening in a mouse model for BCIE. , 1998, The Journal of investigative dermatology.

[22]  C. Byrne,et al.  Patterned acquisition of skin barrier function during development. , 1998, Development.

[23]  P. Elias,et al.  Keratinocyte differentiation is stimulated by activators of the nuclear hormone receptor PPARalpha. , 1998, The Journal of investigative dermatology.

[24]  J. Vonesch,et al.  Spatio-temporally controlled site-specific somatic mutagenesis in the mouse. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[25]  R. Baron,et al.  Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[26]  B. Bernard,et al.  Expression of retinoid nuclear receptor superfamily members in human hair follicles and its implication in hair growth. , 1997, Acta dermato-venereologica.

[27]  P Chambon,et al.  Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains. , 1997, Biochemical and biophysical research communications.

[28]  Tatsuya Yoshizawa,et al.  Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning , 1997, Nature Genetics.

[29]  P. Elias,et al.  Activators of the nuclear hormone receptors PPARalpha and FXR accelerate the development of the fetal epidermal permeability barrier. , 1997, The Journal of clinical investigation.

[30]  E. Fuchs.  Keith R. Porter Lecture, 1996. Of mice and men: genetic disorders of the cytoskeleton. , 1997, Molecular biology of the cell.

[31]  P. Chambon,et al.  In vivo functional analysis of the Hoxa-1 3' retinoic acid response element (3'RARE). , 1997, Development.

[32]  P. Chambon,et al.  Genetic evidence that the retinoid signal is transduced by heterodimeric RXR/RAR functional units during mouse development. , 1997, Development.

[33]  E. Fuchs,et al.  Transgenic studies with a keratin promoter-driven growth hormone transgene: prospects for gene therapy. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[34]  R. Wolf.  Mineral water and spas in Israel. , 1996, Clinics in dermatology.

[35]  J. Sundberg,et al.  Mouse models for the study of human hair loss. , 1996, Dermatologic clinics.

[36]  P Chambon,et al.  Ligand-activated site-specific recombination in mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[37]  P. Chambon,et al.  RXRalpha‐null F9 embryonal carcinoma cells are resistant to the differentiation, anti‐proliferative and apoptotic effects of retinoids. , 1996, The EMBO journal.

[38]  J. Voorhees,et al.  Molecular mechanisms of retinoid actions in skin , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  P. Chambon.  A decade of molecular biology of retinoic acid receptors , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[40]  Y. Liu,et al.  Vitamin D Receptors Repress Basal Transcription and Exert Dominant Negative Activity on Triiodothyronine-mediated Transcriptional Activity (*) , 1996, The Journal of Biological Chemistry.

[41]  Philippe Kastner,et al.  Nonsteroid nuclear receptors: What Are genetic studies telling us about their role in real life? , 1995, Cell.

[42]  K. Umesono,et al.  The nuclear receptor superfamily: The second decade , 1995, Cell.

[43]  F. Watt,et al.  Suprabasal integrin expression in the epidermis of transgenic mice results in developmental defects and a phenotype resembling psoriasis , 1995, Cell.

[44]  R. Steinman,et al.  DEC-205, a 205-kDa protein abundant on mouse dendritic cells and thymic epithelium that is detected by the monoclonal antibody NLDC-145: purification, characterization, and N-terminal amino acid sequence. , 1995, Cellular immunology.

[45]  R. Evans,et al.  A transcriptional co-repressor that interacts with nuclear hormone receptors , 1995, Nature.

[46]  P. Chambon,et al.  In situ detection of retinoid‐X receptor expression in normal and psoriatic human skin , 1995, The British journal of dermatology.

[47]  P. Chambon,et al.  Conditional site-specific recombination in mammalian cells using a ligand-dependent chimeric Cre recombinase. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[48]  L Piana,et al.  CD31 quantitative immunocytochemical assays in breast carcinomas. Correlation with current prognostic factors. , 1995, American journal of clinical pathology.

[49]  Toshihiro Tanaka,et al.  Inhibition of skin development by targeted expression of a dominant-negative retinoic acid receptor , 1995, Nature.

[50]  J. Rothnagel,et al.  Targeting expression of a dominant-negative retinoic acid receptor mutant in the epidermis of transgenic mice results in loss of barrier function. , 1995, Genes & development.

[51]  P. Chambon,et al.  Detection of retinoid X receptors using specific monoclonal and polyclonal antibodies. , 1994, Biochemical and biophysical research communications.

[52]  P. Chambon,et al.  Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants. , 1994, Development.

[53]  J. Reichrath,et al.  Hair follicle expression of 1,25‐dihydroxyvitamin D3 receptors during the murine hair cycle , 1994, The British journal of dermatology.

[54]  J. Vonesch,et al.  Genetic analysis of RXRα developmental function: Convergence of RXR and RAR signaling pathways in heart and eye morphogenesis , 1994, Cell.

[55]  E. Fuchs,et al.  Programming gene expression in developing epidermis. , 1994, Development.

[56]  P. Chambon,et al.  Immunological identification and functional quantitation of retinoic acid and retinoid X receptor proteins in human skin. , 1994, The Journal of biological chemistry.

[57]  R. Evans,et al.  RXR alpha mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis. , 1994, Genes & development.

[58]  J. Gerdes,et al.  The cell proliferation-associated antigen of antibody Ki-67: a very large, ubiquitous nuclear protein with numerous repeated elements, representing a new kind of cell cycle-maintaining proteins , 1993, The Journal of cell biology.

[59]  P. Chambon,et al.  High postnatal lethality and testis degeneration in retinoic acid receptor alpha mutant mice. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[60]  P. Chambon,et al.  Function of retinoic acid receptor γ in the mouse , 1993, Cell.

[61]  James T. Elder,et al.  Differential regulation of retinoic acid receptors and binding proteins in human skin. , 1992, The Journal of investigative dermatology.

[62]  R. Evans,et al.  Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. , 1992, Genes & development.

[63]  M. H. Hardy,et al.  The secret life of the hair follicle. , 1992, Trends in genetics : TIG.

[64]  Philippe Kastner,et al.  Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently , 1992, Cell.

[65]  Timothy A. Springer,et al.  Adhesion receptors of the immune system , 1990, Nature.

[66]  R. Paus,et al.  Telogen skin contains an inhibitor of hair growth , 1990, The British journal of dermatology.

[67]  E. Fuchs,et al.  Tissue-specific and differentiation-specific expression of a human K14 keratin gene in transgenic mice. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[68]  J. Allison,et al.  Limited diversity of γδ antigen receptor genes of thy-1+ dendritic epidermal cells , 1988, Cell.

[69]  R. Volpé.  Ultrastructural Pathology of the Cell and Matrix , 1982 .

[70]  D. Sachs,et al.  Epidermal Langerhans cells are derived from cells originating in bone marrow , 1979, Nature.

[71]  E. F. Dubrul.  Fine structure of epidermal differentiation in the mouse. , 1972, The Journal of experimental zoology.

[72]  B. Bernard,et al.  Thyroid hormone receptor beta1 is expressed in the human hair follicle. , 2000, The British journal of dermatology.

[73]  V. Giguère.  Orphan nuclear receptors: from gene to function. , 1999, Endocrine reviews.

[74]  Philippe Soriano.  Generalized lacZ expression with the ROSA26 Cre reporter strain , 1999, Nature Genetics.

[75]  M. Amling,et al.  Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice. , 1998, Endocrinology.

[76]  P. Chambon,et al.  The RXR α ligand-dependent activation function 2 ( AF2 ) is important for mouse development , 1998 .

[77]  P. Chambon,et al.  Suprabasal expression of a dominant-negative RXR alpha mutant in transgenic mouse epidermis impairs regulation of gene transcription and basal keratinocyte proliferation by RAR-selective retinoids. , 1997, Genes & development.

[78]  J. Sundberg,et al.  Normal biology and aging changes of skin and hair , 1996 .

[79]  P. Chambon,et al.  Abnormal spermatogenesis in RXR beta mutant mice. , 1996, Genes & development.

[80]  T. Hirobe.  Structure and function of melanocytes: microscopic morphology and cell biology of mouse melanocytes in the epidermis and hair follicle. , 1995, Histology and histopathology.

[81]  T. Hirobe.  Structure and function of melanocytes, Microscopic , 1995 .

[82]  R. Ramirez-Solis,et al.  Gene targeting in embryonic stem cells. , 1993, Methods in enzymology.

[83]  J. Y. Chen,et al.  Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. , 1992, Cell.

[84]  T. Doetschman,et al.  Gene targeting in embryonic stem cells. , 1991, Biotechnology.

[85]  J. Allison,et al.  Limited diversity of gamma delta antigen receptor genes of Thy-1+ dendritic epidermal cells. , 1988, Cell.

[86]  S. Gordon,et al.  F4/80, a monoclonal antibody directed specifically against the mouse macrophage , 1981, European journal of immunology.