Ectoderm-Targeted Overexpression of the Glucocorticoid Receptor Induces Hypohidrotic Ectodermal Dysplasia

• Published in: Endocrinology (Philadelphia) Vol. 146; no. 6; pp. 2629 - 2638
• Main Authors: Cascallana, Jose Luis, Bravo, Ana, Donet, Eva, Leis, Hugo, Lara, Maria Fernanda, Paramio, Jesús M, Jorcano, José L, Pérez, Paloma
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01-06-2005
• Subjects: Abnormalities, Multiple - genetics; Abnormalities, Multiple - physiopathology; Alopecia - genetics; Alopecia - physiopathology; Animals; Biological and medical sciences; Dermatology; Disease Models, Animal; Ectodermal Dysplasia - genetics; Ectodermal Dysplasia - physiopathology; Facial bones, jaws, teeth, parodontium: diseases, semeiology; Female; Gene Expression Regulation, Developmental; Hair and nails disorders; Hair Follicle - abnormalities; Keratin-15; Keratin-5; Keratins - genetics; Male; Medical sciences; Mice; Mice, Transgenic; Non tumoral diseases; Otorhinolaryngology. Stomatology; Pregnancy; Receptors, Glucocorticoid - genetics; Skin involvement in other diseases. Miscellaneous. General aspects; Tooth Abnormalities - genetics; Tooth Abnormalities - physiopathology; Anhidrotic ectodermal dysplasia; Hair; Skin disease; Ectoderm; Malformation; Stomatology; Dental disease; Glucocorticoid receptor; Gene overexpression; Sweat gland disease; Genetic disease
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2004-1246

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 κ-enhancer in B cells (NF-κB), which is essential to epithelial homeostasis and development. A number of mouse models bearing disruptions in NF-κB 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-κB activity is greatly decreased due to functional antagonism between GR and NF-κB. 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 κB kinase subunits, IKKα and IKKγ, and diminished p65 protein levels in K5-GR embryonic tooth, resulting in a significantly reduced κB-binding activity. Remarkably, altered NF-κB activity elicited by GR overexpression correlated with a dramatic decrease in the protein levels of ΔNp63 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-κB and p63 dysfunction may provide important clues to understanding the basis of other ectodermal dysplasia syndromes.