Targeted Skin Overexpression of the Mineralocorticoid Receptor in Mice Causes Epidermal Atrophy, Premature Skin Barrier Formation, Eye Abnormalities, and Alopecia

Yannis Sainte Marie^*, Antoine Toulon^*, Ralf Paus, Eve Maubec, Aicha Cherfa^*, Maggy Grossin, Vincent Descamps, Maud Clemessy^¶, Jean-Marie Gasc^¶, Michel Peuchmaur^||, Adam Glick^**, Nicolette Farman^* and Frederic Jaisser^*

From INSERM U772,^* Collège de France, Université Paris-Descartes, Paris, France; the Department of Dermatology, University Hospital Schleswig-Holstein, University of Luebeck, Luebeck, Germany; the Service de Dermatologie, Hôpital Bichat, Paris, France; the Service d’Anatomopathologie, Hôpital Louis Mourier, Colombes, France; INSERM U833,^¶ Collège de France, Paris, France; the Equipe EA 3102, || Service d’Anatomopathologie, Hôpital Robert Debré, Paris, France; and Center for Molecular Toxicology and Carcinogenesis,^*^* Pennsylvania State University, University Park, Pennsylvania

The mineralocorticoid receptor (MR) is a transcription factorof the nuclear receptor family, activation of which by aldosteroneenhances salt reabsorption in the kidney. The MR is also expressedin nonclassical aldosterone target cells (brain, heart, andskin), in which its functions are incompletely understood. Toexplore the functional importance of MR in mammalian skin, wehave generated a conditional doxycycline-inducible model ofMR overexpression, resulting in double-transgenic (DT) mice[keratin 5-tTa/tetO-human MR (hMR)], targeting the human MRspecifically to keratinocytes of the epidermis and hair follicle(HF). Expression of hMR throughout gestation resulted in earlypostnatal death that could be prevented by antagonizing MR signaling.DT mice exhibited premature epidermal barrier formation at embryonicday 16.5, reduced HF density and epidermal atrophy, increasedkeratinocyte apoptosis at embryonic day 18.5, and prematureeye opening. When hMR expression was initiated after birth toovercome mortality, DT mice developed progressive alopecia andHF cysts, starting 4 months after hMR induction, preceded bydystrophy and cycling abnormalities of pelage HF. In contrast,interfollicular epidermis, vibrissae, and footpad sweat glandsin DT mice were normal. This new mouse model reveals novel biologicalroles of MR signaling and offers an instructive tool for dissectingnonclassical functions of MR signaling in epidermal, hair follicle,and ocular physiology.