Ectoderm-targeted overexpression of the glucocorticoid receptor induces hypohidrotic ectodermal dysplasia.

Hypohidrotic ectodermal dysplasia is a human syndrome defined by maldevelopment of one or more ectodermal-derived tissues, including the epidermis and cutaneous appendices, teeth, and exocrine glands. The molecular bases of this pathology converge in a dysfunction of the transcription factor nuclear factor of the kappa-enhancer in B cells (NF-kappaB), which is essential to epithelial homeostasis and development. A number of mouse models bearing disruptions in NF-kappaB signaling have been reported to manifest defects in ectodermal derivatives. In ectoderm-targeted transgenic mice overexpressing the glucocorticoid receptor (GR) [keratin 5 (K5)-GR mice], the NF-kappaB activity is greatly decreased due to functional antagonism between GR and NF-kappaB. Here, we report that K5-GR mice exhibit multiple epithelial defects in hair follicle, tooth, and palate development. Additionally, these mice lack Meibomian glands and display underdeveloped sweat and preputial glands. These phenotypic features appear to be mediated specifically by ligand-activated GR because the synthetic analog dexamethasone induced similar defects in epithelial morphogenesis, including odontogenesis, in wild-type mice. We have focused on tooth development in K5-GR mice and found that an inhibitor of steroid synthesis partially reversed the abnormal phenotype. Immunostaining revealed reduced expression of the inhibitor of kappaB kinase subunits, IKKalpha and IKKgamma, and diminished p65 protein levels in K5-GR embryonic tooth, resulting in a significantly reduced kappaB-binding activity. Remarkably, altered NF-kappaB activity elicited by GR overexpression correlated with a dramatic decrease in the protein levels of DeltaNp63 in tooth epithelia without affecting Akt, BMP4, or Foxo3a. Given that many of the 170 clinically distinct ectodermal dysplasia syndromes still remain without cognate genes, deciphering the molecular mechanisms of this mouse model with epithelial NF-kappaB and p63 dysfunction may provide important clues to understanding the basis of other ectodermal dysplasia syndromes.

[1]  A. Smahi,et al.  The NF-kappaB signalling pathway in human diseases: from incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes. , 2002, Human molecular genetics.

[2]  I. Thesleff,et al.  Ectodysplasin signaling in development. , 2003, Cytokine & growth factor reviews.

[3]  I. Verma,et al.  IKK1-deficient mice exhibit abnormal development of skin and skeleton. , 1999, Genes & development.

[4]  J. Cidlowski,et al.  The glucocorticoid receptor: coding a diversity of proteins and responses through a single gene. , 2002, Molecular endocrinology.

[5]  T. Slaga,et al.  Disruption of eyelid and cornea development by targeted overexpression of the glucocorticoid receptor. , 2003, The International journal of developmental biology.

[6]  P. Eustace,et al.  Absent meibomian glands: A marker for EEC syndrome , 1996, Eye.

[7]  G. Chrousos,et al.  Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. , 1996, Endocrine reviews.

[8]  V. Godfrey,et al.  Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. , 2000, Molecular cell.

[9]  Increased fetal glucocorticoid exposure delays puberty onset in postnatal life. , 2000, Endocrinology.

[10]  M. Karin,et al.  A Dual Role for Ikkα in Tooth Development , 2004 .

[11]  M. Hild,et al.  Zebrafish DeltaNp63 is a direct target of Bmp signaling and encodes a transcriptional repressor blocking neural specification in the ventral ectoderm. , 2002, Developmental cell.

[12]  C. Lau,et al.  Glucocorticoid receptor expression during the development of the embryonic mouse secondary palate. , 1994, Journal of craniofacial genetics and developmental biology.

[13]  G. Haegeman,et al.  The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-1: molecular mechanisms for gene repression. , 2003, Endocrine reviews.

[14]  Klaus Rajewsky,et al.  NEMO/IKKγ-Deficient Mice Model Incontinentia Pigmenti , 2000 .

[15]  W. Birchmeier,et al.  Requirement of NF-kappaB/Rel for the development of hair follicles and other epidermal appendices. , 2001, Development.

[16]  J. Donahue,et al.  Hidrotic ectodermal dysplasia with corneal involvement. , 1999, Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus.

[17]  Swaroop Aradhya,et al.  NF-κB signaling and human disease , 2001 .

[18]  R. Foos,et al.  Absent meibomian glands in the ectrodactyly, ectodermal dysplasia, cleft lip-palate syndrome. , 1984, American journal of ophthalmology.

[19]  Geert J. P. L. Kops,et al.  Direct control of the Forkhead transcription factor AFX by protein kinase B , 1999, Nature.

[20]  K A Matkowskyj,et al.  Quantitative Immunohistochemistry by Measuring Cumulative Signal Strength Using Commercially Available Software Photoshop and Matlab , 2000, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[21]  J. Orange,et al.  Finding NEMO: genetic disorders of NF-κB activation , 2003 .

[22]  R. Paus,et al.  Glucocorticoid effect on hair growth initiation: a reconsideration. , 1993, Skin pharmacology : the official journal of the Skin Pharmacology Society.

[23]  A. Shevchenko,et al.  Activation of Transcription Factor NF-κB Requires ELKS, an IκB Kinase Regulatory Subunit , 2004, Science.

[24]  Michael Karin,et al.  Activation by IKKα of a Second, Evolutionary Conserved, NF-κB Signaling Pathway , 2001, Science.

[25]  J. Pietenpol,et al.  ΔNp63α Expression Is Regulated by the Phosphoinositide 3-Kinase Pathway* , 2003, Journal of Biological Chemistry.

[26]  A. Vaahtokari,et al.  Regulation of organogenesis. Common molecular mechanisms regulating the development of teeth and other organs. , 1995, The International journal of developmental biology.

[27]  R. Gaynor,et al.  IκB kinases: key regulators of the NF-κB pathway , 2004 .

[28]  A. Fischer,et al.  A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency , 2003 .

[29]  J. Lamartine.  Towards a new classification of ectodermal dysplasias , 2003, Clinical and experimental dermatology.

[30]  T. Slaga,et al.  Altered skin development and impaired proliferative and inflammatory responses in transgenic mice overexpressing the glucocorticoid receptor , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[31]  M. Karin,et al.  IkappaB kinase alpha is essential for development of the mammalian cornea and conjunctiva. , 2000, Investigative ophthalmology & visual science.

[32]  M. Karin,et al.  IKKα controls formation of the epidermis independently of NF-κB , 2001, Nature.

[33]  Ryuji Kobayashi,et al.  IκB Kinase Promotes Tumorigenesis through Inhibition of Forkhead FOXO3a , 2004, Cell.

[34]  J. Jorcano,et al.  Glucocorticoid Receptor Counteracts Tumorigenic Activity of Akt in Skin through Interference with the Phosphatidylinositol 3-Kinase Signaling Pathway. , 2004, Molecular endocrinology.

[35]  J. Jorcano,et al.  Abnormal epidermal differentiation and impaired epithelial-mesenchymal tissue interactions in mice lacking the retinoblastoma relatives p107 and p130 , 2003, Development.

[36]  P. Sharpe,et al.  Transformation of tooth type induced by inhibition of BMP signaling. , 1998, Science.

[37]  Michael Karin,et al.  The IKK NF-κB system: a treasure trove for drug development , 2004, Nature Reviews Drug Discovery.