Cathepsin L deficiency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling

Lysosomal cysteine proteinases of the papain family are involved in lysosom al bulk proteolysis, major histocompatibility complex class II mediated ant igen presentation, prohormone processing, and extracellular matrix remodeli ng. 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 ce lls. CTSL-deficient mice develop periodic hair loss and epidermal hyperplas ia, 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 ep ithelial cells and basal epidermal keratinocytes-both of ectodermal origin- are the primary characteristics underlying the mutant phenotype. Pathologic al inflammatory responses have been excluded as a putative cause of the ski n and hair disorder. The phenotype of CTSL-deficient mice is reminiscent of the spontaneous mouse mutant furless (fs). Analyses of the cfsl gene of fs mice revealed a G149R mutation inactivating the proteinase activity. CTSL is the first lysosomal proteinase shown to be essential for epidermal homeo stasis id regular hair follicle morphogenesis and cycling.