Notch signaling in bulge stem cells is not required for selection of hair follicle fate

Abstract

Notch signaling plays an important role in hair follicle maintenance, and it has been suggested that Notch is also required for follicular fate selection by adult hair follicle stem cells in the bulge. Here we demonstrate that, on the contrary, Notch signaling in bi-potential bulge stem cells or their uncommitted descendents acts to suppress the epidermal fate choice, thus ensuring follicular fate selection. To examine the role of Notch signaling in adult hair follicle stem cells, we used a Krt1-15-CrePR1 transgenic mouse line to delete Rbpj or all Notch proteins specifically in the bulge stem cells. We conclusively determined that in the absence of Notch signaling,bulge stem cell descendents retain their capacity to execute the follicular differentiation program but fail to maintain it owing to their genetic deficiency. The defect in terminal differentiation caused the diversion of Notch-deficient hair follicles to epidermal cysts, and the presence of wild-type cells could not prevent this conversion. Importantly, our analysis revealed that a functional Notch signaling pathway was required to block bulge stem cells from migrating into, and assuming the fate of, interfollicular epidermis. Taken together, our findings yield detailed insight into the function of Notch signaling in hair follicle stem cells and reveal the mechanism of the replacement of Notch-deficient adult hair follicles by epidermal cysts.

Keratin 79 identifies a novel population of migratory epithelial cells that initiates hair canal morphogenesis and regeneration

“…3B), whereas dnMAMLexpressing cells extended out into the epidermis (Fig. 6C), which is reminiscent of previous findings that perturbing Notch causes bulge cells to depart from their niche (Demehri and Kopan, 2009 (Thiboutot, 2008;Zaenglein et al, 2012). Early acne lesions develop cyst-like structures known as comedones (Fig.…”

“…Disruption of Notch activity in the skin, either by genetic ablation of Notch pathway components or by expression of dominant-negative GFP-tagged mastermind-like 1 (dnMAML), can induce widespread cyst formation (Blanpain et al, 2006;Demehri and Kopan, 2009;Dumortier et al, 2010;Pan et al, 2004;Proweller et al, 2006;Vauclair et al, 2005;Yamamoto et al, 2003). To determine whether Notch is required to maintain the INF, we generated mice expressing Lrig1-Cre ERT2 and a Cre-inducible dnMAML cassette under the control of the ROSA26 promoter (Lrig1;dnMAML).…”

Notch signaling represses p63 expression in the developing surface ectoderm

“…As the four Notch receptors and ligands are redundant (Kitamoto et al, 2005;Krebs et al, 2000;Pan et al, 2004), several receptors or ligands must be deleted simultaneously to generate phenotypes in many systems. Additionally, conditional deletion of Notch components within the skin has been performed 3783 RESEARCH ARTICLE Notch maintains ectoderm fate using keratin promoters, which act after p63 expression is initiated Demehri and Kopan, 2009). Interestingly, Presenilin genes have been conditionally deleted in a mosaic pattern within the surface ectoderm using mice expressing Cre driven by the Msx2 promoter, which is active around E9.5, but the expression of p63 was not examined in these mice (Pan et al, 2004).…”

“…Alternatively, non-canonical Notch signaling may be involved by interacting with alternative signaling pathways such as FGF, Shh and Wnt signaling (Sanalkumar et al, 2010). Noncanonical Notch signaling in the skin occurs given the different phenotypes of conditional genetic mouse models lacking a functional γ-secretase complex (presenelin 1/2; PS1/PS2), the Notch receptors (Notch1/2; N1/N2) or the RBP-Jk transcriptional repressor (Demehri and Kopan, 2009). In a similar fashion, p63 may negatively regulate Notch signaling pathway.…”

Biology of Human Hair: Know Your Hair to Control It

“…In the absence of Notch signaling, the hair shaft still forms and contains appropriately positioned cells expressing markers for each fate; however, because IRS cells fail to adhere to each other, the follicular architecture cannot be sustained, which leads to the transformation of these aberrant HF into epidermal cysts [92][93][94][95]. Very recently, Demehri and Kopan [96] proposed that Notch acting on bi-potential bulge stem cells, or their uncommitted migratory descendents, plays an inhibitory role in preventing bulge stem cells from differentiating into epidermal cells, thus ensuring the follicular fate.…”