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

Abstract

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.

Death penalty for keratinocytes: apoptosis versus cornification

“…The importance of cathepsins in skin formation is also reflected in other cathepsin knockout studies revealing that normal epidermal homeostasis and hair follicle formation require cathepsin L. 76 The mutant furless and nackt mice, which show defects in hair follicle development, have an inactivating mutation in the cathepsin L gene. 76 Genetic mapping revealed that the mutations in the autosomal recessive Papillon-Lefevre syndrome, marked by premature tooth loss and palmoplantar keratosis, result in loss-of-function of the cathepsin C gene.…”

“…76 Genetic mapping revealed that the mutations in the autosomal recessive Papillon-Lefevre syndrome, marked by premature tooth loss and palmoplantar keratosis, result in loss-of-function of the cathepsin C gene. 77 Furthermore, cathepsin L2 has been detected in stratum corneum extracts.…”

Asparagine Endopeptidase Is Not Essential for Class II MHC Antigen Presentation but Is Required for Processing of Cathepsin L in Mice

“…Generation of class II MHC-, Cat B-, Cat L-, Cat S-, and AEP-deficient mice has been described previously (9,15,(23)(24)(25). Cat Land Cat B-deficient mice were backcrossed to the C57BL/6J background for five to six generations.…”

PIASy-Deficient Mice Display Modest Defects in IFN and Wnt Signaling

“…For electroporation of D3 embryonic stem cells the targeting vector was linearized with SalI. Electroporation and selection of embryonic stem (ES) cells and the processing of G418-resistant ES cell clones were performed as described (49). Homologous recombination was identified by DNA blot analysis with internal, 5Ј and 3Ј external probes (see Fig.…”