The Role of LEKTI in the Fate Determination of Keratinocyte Stem Cells

SPINK5 (serine protease inhibitor Kazal-type 5) encodes the proteinase inhibitor LEKTI (lympho-epithelial Kazal-type related inhibitor). In skin, LEKTI expression is restricted to the stratum granulosum of the epidermis and the inner root sheath of hair follicles. Mutations that create premature termination codons in SPINK5 have been reported as the cause of Netherton syndrome (NS), a human autosomal recessive disorder characterized by congenital ichthyosis with defective cornification, a specific hair shaft defect known as trichorrexis invaginata or "bamboo hair", and severe atopic manifestations, including atopic dermatitis and hayfever. Spink5 knockout mice display a similar phenotype, but die at birth due to severe dehydration. In order to follow the effects of Spink5 knockout in the skin over a longer period of time, Descargues, Barrandon and colleagues transplanted whole back skin from Spink5-/- newborn mice onto the back of nude mice. Surprisingly, psoriasis-like hyperplasia, basement membrane breakdown followed by invasion of spindle-shaped epidermal cells into the dermal compartment, and formation of numerous sweat gland-like structures were observed in the grafts. These observations suggested a new role for LEKTI on the proliferation and fate determination of keratinocyte stem cells. The work described in this thesis aims to investigate the mechanisms by which LEKTI can impact these biological processes, using clonogenic keratinocytes isolated from patients with NS, and Spink5-downregulated hair follicle multipotent stem cells of the rat. I show that membrane-bounded enzymes FURIN and TACE (tumor necrosis factor alpha converting enzyme or ADAM17) are potential targets of the LEKTI inhibitory activity. Moreover, I demonstrate that prominent cleavage of EDA (Ectodysplasin A) and TNFα (tumor necrosis factor alpha), proteins activated by FURIN and TACE, respectively, is observed in the absence of LEKTI. Altogether, my results thoroughly support the hypothesis that LEKTI may act as a regulator node in several signaling pathways involved in epidermal stem cell behavior.


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