Notch signaling regulates a variety of processes such as differentiation, proliferation, apoptosis, and cell fate choice. Notch ligand binds to Notch receptor results in the release and translocation of activated Notch (NICD) into the nucleus. NICD binds to Rbpj and Mastermind, thereby activating downstream target genes. Protein O-fucose transferase-1 (Pofut1), one of the Notch receptor modifiers which catalyzes O-fucose modification of Notch receptor extracellular domain, is crucial for ligand-receptor interactions. Notch signaling has been shown to regulate early-stage differentiation of the epidermis and complete maturation of hair follicles; however, how Notch signaling participates in epidermal barrier and postnatal hair cycle homeostasis are less studied. Here, we applied Cre/loxP system to generate conditional knockout (cKO) of Pofut1 and Rbpj in hair follicle lineages and suprabasal epidermis using Tgfb3-Cre deleter. Rbpj and Pofut1 cKO mice can survive after birth and both displayed defects in the granular layer and reactive epidermal hyperplasia. Rbpj cKO mice can only live up to two weeks, whereas Pofut1 cKO mice stay alive for 3-4 months and displayed atopic-dermatitis disease. Interestingly, Pofut1 cKO mice displayed ultrastructural abnormalities in the granular layer and altered filaggrin processing in the epidermis, suggesting a perturbation of the late-stage epidermal differentiation. Examination of certain proteases and protease inhibitors involved in filaggrin processing revealed elevated expression levels of caspase 14 and kallikrein-related peptidase in the mutant epidermis. Disruption of Pofut1 in hair follicle lineages resulted in aberrant telogen morphology, concomitant with a decrease of bulge stem cell markers and an increase of K14-positive keratinocytes in mutant hair follicles. To investigate the effect of Notch signlaing loss on the stemness of hair follicle stem cells, we are currently studying the impact of bulge-specific deletion of Pofut1 and Rbpj on hair follicle stem cells. Our data suggest that Notch signaling plays a role in epidermal and hair cycle homeostasis.
Date:
2013-05
Relation:
Journal of Investigative Dermatology. 2013 May;133:S116.
