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

Department of Animal Pathology, Veterinary Faculty (J.L.C., A.B., H.L.), University of Santiago de Compostela, E-27002 Lugo; Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Cientifica (IBV-CSIC) (E.D., H.L., P.P.), E-46010 Valencia; Project on Cell and Molecular Biology and Gene Therapy (J.M.P., J.L.J.), Centro de Investigaciones Energeticas Medioambientales y Tecnologicas, E-28040 Madrid; and Fundación Valenciana de Investigaciones Biomédicas (FVIB) (E.D., H.L., P.P.), 46013 Valencia, Spain

Address all correspondence and requests for reprints to: Paloma Pérez, Laboratory of Animal Models, Genomics and Pharmacoproteomics Program, Fundación Valenciana de Investigaciones Biomédicas, Avenida Autopista del Saler 16, Camino de las Moreras, E-46013 Valencia, Spain. E-mail: pperez{at}ochoa.fib.es.

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 -enhancer in B cells (NF-B), which is essential to epithelial homeostasis and development. A number of mouse models bearing disruptions in NF-B 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-B activity is greatly decreased due to functional antagonism between GR and NF-B. 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 B kinase subunits, IKK and IKK, and diminished p65 protein levels in K5-GR embryonic tooth, resulting in a significantly reduced B-binding activity. Remarkably, altered NF-B activity elicited by GR overexpression correlated with a dramatic decrease in the protein levels of Np63 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-B and p63 dysfunction may provide important clues to understanding the basis of other ectodermal dysplasia syndromes.

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