Impaired Hair Follicle Morphogenesis and Cycling with Abnormal Epidermal Differentiation in nackt Mice, a Cathepsin L-Deficient Mutation

Abstract

We previously described an autosomal-recessive mutation named nackt (nkt) exhibiting partial alopecia associated with CD4(+) T-cell deficiency. Also, we recently reported that nkt (now Ctsl(nkt)) comprises a deletion in the cathepsin L (Ctsl) gene. Another recent study reported that Ctsl knockout mice have CD4(+) T-cell deficiency and periodic shedding of hair, which recapitulate the nkt mutation and the old furless (fs) mutation. The current study focuses on the dermatological aspects of the nkt mutation. Careful histological analysis of skin development of homozygous nkt mice revealed a delayed hair follicle morphogenesis and late onset of the first catagen stage. The skin of Ctsl(nkt)/Ctsl(nkt) mice showed mild epidermal hyperplasia and hyperkeratosis, severe hyperplasia of the sebaceous glands, and structural alterations of hair follicles. Epidermal differentiation seems to be affected in nkt skin, with overexpression of involucrin and profilaggrin/filaggrin along with focal areas of keratin 6 expression in the interfollicular epidermis. Severe epidermal hyperplasia, acanthosis, orthokeratosis, and hyperkeratosis were only observed in mice maintained in nonpathogen-free environments. The analysis of Rag2-/- Ctsl(nkt)/Ctsl(nkt) double-mutant mice indicates that the skin defect remains under the absence of T and B cells. This animal model provides in vivo evidence that cysteine protease cathepsin L plays a critical role in hair follicle morphogenesis and cycling, as well as epidermal differentiation.

Normal Fur Development and Sebum Production Depends on Fatty Acid 2-Hydroxylase Expression in Sebaceous Glands

“…As it has been shown for asebia mice, Ctsl Ϫ/Ϫ mice have a prolonged anagen phase/delayed catagen entry (48,50). Similarly, preliminary data suggest a prolonged growing phase (morphogenesis and anagen) also in Fa2h Ϫ/Ϫ mice.…”

The lysosomal cysteine protease cathepsin L regulates keratinocyte proliferation by control of growth factor recycling

“…However, there is growing evidence for specific intra-and extracellular functions for CTSL in MHC-II antigen presentation (Honey and Rudensky, 2003), prohormone processing (Friedrichs et al, 2003;Yasothornsrikul et al, 2003) and other processes involving limited proteolysis (Turk et al, 2001). Major insights into the function of cathepsin L in the skin result from analysis of mice with targeted inactivation of the CTSL gene (ctsl -/-mice) and from the spontaneous mouse mutations nackt (ctsl nkt /ctsl nkt ) and furless (fs -/fs -) for which the cathepsin L gene has been identified as the target (Benavides et al, 2002;Roth et al, 2000). Cathepsin L-deficient (ctsl -/-) mice develop periodic hair loss, gingival acanthosis and epidermal hyperplasia with hyperkeratosis (Nishimura et al, 2002;Tobin et al, 2002).…”

“…Impaired differentiation of hair follicle epithelial cells and hyperproliferation of basal epidermal keratinocytes are the primary characteristics of the ctsl -/-phenotype. Organ cultures of neonatal ctsl -/-mouse skin and crossing of Rag2 -/-mice with ctsl nkt /ctsl nkt mice (Benavides et al, 2002) revealed that the skin phenotype is independent of systemic, i.e. immunological, effects.…”

Loss of responsiveness to IGF-I in cells with reduced cathepsin L expression levels

“…They are involved in proteolytic processing of proteins in the endocytic pathway, including peptide growth factors that are internalized in a complex with their plasma membrane receptors (Authier et al, 1999). Recent studies with CathLdeficient mice have implicated this enzyme in several developmental processes, including epidermal homeostasis and hair follicle development (Reinheckel et al, 2001;Benavides et al, 2002).…”