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* Institut für Molekulare Medizin und Zellforschung, Albert Ludwigs Universität Freiburg, 79106 Freiburg, Germany;
Hautklinik, Charité, Humboldt Universität, 10117 Berlin, Germany;
Abteilung Biochemie II, Zentrum Biochemie und Molekulare Zellbiologie, Georg August Universität Göttingen, 37073 Göttingen, Germany;
§ Allgemeine Pathologie und Neuropathologie, Tierärztliche Fakultät der Ludwig Maximilians Universität München, 80539 München, Germany; and
¶ Institut für Ultrastrukturforschung der Haut, Hautklinik der Ruprecht Karls Universität Heidelberg, 69115 Heidelberg, Germany
5Correspondence: Institut für Molekulare Medizin und Zellforschung, Albert Ludwigs Universität Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany. E-mail: petersc{at}mm11.ukl.uni-freiburg.de
Lysosomal cysteine proteinases of the papain family are involved in lysosomal bulk proteolysis, major histocompatibility complex class II mediated antigen presentation, prohormone processing, and extracellular matrix remodeling. Cathepsin L (CTSL) is a ubiquitously expressed major representative of the papain-like family of cysteine proteinases. To investigate CTSL in vivo functions, the gene was inactivated by gene targeting in embryonic stem cells. CTSL-deficient mice develop periodic hair loss and epidermal hyperplasia, acanthosis, and hyperkeratosis. The hair loss is due to alterations of hair follicle morphogenesis and cycling, dilatation of hair follicle canals, and disturbed club hair formation. Hyperproliferation of hair follicle epithelial cells and basal epidermal keratinocytes—both of ectodermal origin—are the primary characteristics underlying the mutant phenotype. Pathological inflammatory responses have been excluded as a putative cause of the skin and hair disorder. The phenotype of CTSL-deficient mice is reminiscent of the spontaneous mouse mutant furless (fs). Analyses of the ctsl gene of fs mice revealed a G149R mutation inactivating the proteinase activity. CTSL is the first lysosomal proteinase shown to be essential for epidermal homeostasis and regular hair follicle morphogenesis and cycling.—Roth, W., Deussing, J., Botchkarev, V. A., Pauly-Evers, M., Saftig, P., Hafner, A., Schmidt, P., Schmahl, W., Scherer, J., Anton-Lamprecht, I., von Figura, K., Paus, R., Peters, C. Cathepsin L deficiency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling.
Key Words: epidermal hyperplasia • hair follicle development • lysosomal cysteine proteinase
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