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This version published online on March 3, 2005
Endocrinology, doi:10.1210/en.2004-1246
A more recent version of this article appeared on June 1, 2005
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Submitted on September 21, 2004
Accepted on February 7, 2005

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

Jose Luis Cascallana, Ana Bravo, Eva Donet, Hugo Leis, MS Fernanda Lara, Jesús M. Paramio, José L. Jorcano, and Paloma Pérez*

Department of Animal Pathology, Veterinary Faculty, University of Santiago de Compostela, E-27002 Lugo (Spain); Instituto de Biomedicina de Valencia IBV-CSIC. Jaime Roig 11, E-46010 Valencia (Spain); Project on Cell and Molecular Biology and Gene Therapy, CIEMAT. Av. Complutense 22, E-28040 Madrid (Spain)

* To whom correspondence should be addressed. E-mail: pperez{at}ochoa.fib.es.

Hypohidrotic ectodermal dysplasia (HED) 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 NF-{kappa}B which is essential to epithelial homeostasis and development. A number of mouse models bearing disruptions in NF-{kappa}B signaling have been reported to manifest defects in ectodermal derivatives. In ectoderm-targeted transgenic mice overexpressing the glucocorticoid receptor (K5-GR mice), the NF-{kappa}B activity is greatly decreased due to functional antagonism between GR and NF-{kappa}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 since the synthetic analog dexamethasone (Dex) 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 I{kappa}B kinase subunits, IKK{alpha} and IKK{gamma}, and diminished p65 protein levels in K5-GR embryonic tooth resulting in a significantly reduced {kappa}B-binding activity. Remarkably, altered NF-{kappa}B activity elicited by GR overexpression correlated with a dramatic decrease in the protein levels of {Delta}Np63 in tooth epithelia without affecting Akt, BMP4 or Foxo3a. Given that many of the 170 clinically distinct ED syndromes still remain without cognate genes, deciphering the molecular mechanisms of this mouse model with epithelial NF-{kappa}B and p63 dysfunction, may provide important clues to understand the basis of other ED syndromes.
Key words: glucocorticoid receptor • NF-{kappa}B signaling • I{kappa}B kinase • transgenic mice • epithelial morphogenesis • ectodermal dysplasia




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