Lee J, Basak JM, Demehri S et al.Bi-compartmental communication contributes to the opposite proliferative behavior of Notch1-deficient hair follicle and epidermal keratinocytes. Development 134:2795-2806

Department of Developmental Biology , Stanford University, Palo Alto, California, United States
Development (Impact Factor: 6.46). 09/2007; 134(15):2795-806. DOI: 10.1242/dev.02868
Source: PubMed


Notch1-deficient epidermal keratinocytes become progressively hyperplastic and eventually produce tumors. By contrast, Notch1-deficient hair matrix keratinocytes have lower mitotic rates, resulting in smaller follicles with fewer cells. In addition, the ratio of melanocytes to keratinocytes is greatly reduced in hair follicles. Investigation into the underlying mechanism for these phenotypes revealed significant changes in the Kit, Tgfbeta and insulin-like growth factor (IGF) signaling pathways, which have not been previously shown to be downstream of Notch signaling. The level of Kitl (Scf) mRNA produced by Notch1-deficient follicular keratinocytes was reduced when compared with wild type, resulting in a decline in melanocyte population. Tgfbeta ligands were elevated in Notch1-deficient keratinocytes, which correlated with elevated expression of several targets, including the diffusible IGF antagonist Igfbp3 in the dermal papilla. Diffusible stromal targets remained elevated in the absence of epithelial Tgfbeta receptors, consistent with paracrine Tgfbeta signaling. Overexpression of Igf1 in the keratinocyte reversed the phenotype, as expected if Notch1 loss altered the IGF/insulin-like growth factor binding protein (IGFBP) balance. Conversely, epidermal keratinocytes contained less stromal Igfbp4 and might thus be primed to experience an increase in IGF signaling as animals age. These results suggest that Notch1 participates in a bi-compartmental signaling network that controls homeostasis, follicular proliferation rates and melanocyte population within the skin.

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    • "During embryonic and adult follicle formation, the activation of signaling pathways such as WNT, tumor growth factor b (TGFb), and fibroblast growth factor (FGF), and the inhibition of BMP signaling in follicle stem cells are essential (Hsu and Fuchs, 2012; Sennett and Rendl, 2012; Lee and Tumbar, 2012). Similarly , during active hair growth, WNT, FGF, Notch, and BMP signaling in matrix progenitor cells is important for successful differentiation into the outgrowing hair shaft (Andl et al., 2004; DasGupta and Fuchs, 1999; Kobielak et al., 2003; Kulessa et al., 2000; Lee et al., 2007). While the essential roles of these signaling pathways have been extensively studied in epithelial stem cells/progenitors, direct genetic testing of DP niche signals has been lacking until very recently (Enshell-Seijffers et al., 2010) due to the long-standing absence of gene ablation tools for the Figure 1 "
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    ABSTRACT: How dermal papilla (DP) niche cells regulate hair follicle progenitors to control hair growth remains unclear. Using Tbx18 Cre to target embryonic DP precursors, we ablate the transcription factor Sox2 early and efficiently, resulting in diminished hair shaft outgrowth. We find that DP niche expression of Sox2 controls the migration speed of differentiating hair shaft progenitors. Transcriptional profiling of Sox2 null DPs reveals increased Bmp6 and decreased BMP inhibitor Sostdc1, a direct Sox2 transcriptional target. Subsequently, we identify upregulated BMP signaling in knockout hair shaft progenitors and demonstrate that Bmp6 inhibits cell migration, an effect that can be attenuated by Sostdc1. A shorter and Sox2-negative hair type lacks Sostdc1 in the DP and shows reduced migration and increased BMP activity of hair shaft progenitors. Collec-tively, our data identify Sox2 as a key regulator of hair growth that controls progenitor migration by fine-tuning BMP-mediated mesenchymal-epithelial crosstalk.
    Developmental Cell 11/2012; 23(5). DOI:10.1016/j.devcel.2012.10.013 · 9.71 Impact Factor
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    • "Additional growth factors Wnt3a and BMP6 are sufficient to maintain the DP hair inductive function (Kishimoto et al. 2000; Rendl et al. 2008), and DP-specific b-catenin/Wnt signaling plays a role in sustaining anagen hair growth and new hair induction in the first postnatal hair cycle (Enshell-Seijffers et al. 2010a,b). Other factors such as DP-specific Notch–Wnt5a signaling facilitate hair follicle differentiation (Lee et al. 2007; Estrach et al. 2008; Hu et al. 2010). "
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    ABSTRACT: During hair follicle morphogenesis, dermal papillae (DPs) function as mesenchymal signaling centers that cross-talk with overlying epithelium to regulate morphogenesis. While the DP regulates hair follicle formation, relatively little is known about the molecular basis of DP formation. The morphogen Sonic hedgehog (Shh) is known for regulating hair follicle epithelial growth, with excessive signaling resulting in basal cell carcinomas. Here, we investigate how dermal-specific Shh signaling contributes to DP formation and hair growth. Using a Cre-lox genetic model and RNAi in hair follicle reconstitution assays, we demonstrate that dermal Smoothened (Smo) loss of function results in the loss of the DP precursor, the dermal condensate, and a stage 2 hair follicle arrest phenotype reminiscent of Shh(-/-) skin. Surprisingly, dermal Smo does not regulate cell survival or epithelial proliferation. Rather, molecular screening and immunostaining studies reveal that dermal Shh signaling controls the expression of a subset of DP-specific signature genes. Using a hairpin/cDNA lentiviral system, we show that overexpression of the Shh-dependent gene Noggin, but not Sox2 or Sox18, can partially rescue the dermal Smo knockdown hair follicle phenotype by increasing the expression of epithelial Shh. Our findings suggest that dermal Shh signaling regulates specific DP signatures to maintain DP maturation while maintaining a reciprocal Shh-Noggin signaling loop to drive hair follicle morphogenesis.
    Genes & development 06/2012; 26(11):1235-46. DOI:10.1101/gad.187401.112 · 10.80 Impact Factor
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    • "We also found increased levels of Ltbp1 mRNA, which is consistent with previous finding demonstrating that expression of TGF-ß is coordinately regulated with that of latent TGF-β-binding proteins [31]. The increases in TGF-ß expression appear to have functional implications, as we also detected elevated levels of direct TGF-ß targets, such as Igfbp4 and Igfpb7, which encode the insulin-like growth factor (IGF)-binding proteins 4 and 7. IGF plays important roles in keratinocyte proliferation, survival, hair follicle growth and epidermal repair following mechanical or UV-induced damage [32], [33]. ILK-deficient epidermis also exhibits increased levels of IGF receptor 1 (Igfr1) and FGF receptor 1 (Fgfr1) mRNAs. "
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    ABSTRACT: Integrin-linked kinase (ILK) is an important scaffold protein that mediates a variety of cellular responses to integrin stimulation by extracellular matrix proteins. Mice with epidermis-restricted inactivation of the Ilk gene exhibit pleiotropic phenotypic defects, including impaired hair follicle morphogenesis, reduced epidermal adhesion to the basement membrane, compromised epidermal integrity, as well as wasting and failure to thrive leading to perinatal death. To better understand the underlying molecular mechanisms that cause such a broad range of alterations, we investigated the impact of Ilk gene inactivation on the epidermis transcriptome. Microarray analysis showed over 700 differentially regulated mRNAs encoding proteins involved in multiple aspects of epidermal function, including keratinocyte differentiation and barrier formation, inflammation, regeneration after injury, and fundamental epidermal developmental pathways. These studies also revealed potential effects on genes not previously implicated in ILK functions, including those important for melanocyte and melanoblast development and function, regulation of cytoskeletal dynamics, and homeobox genes. This study shows that ILK is a critical regulator of multiple aspects of epidermal function and homeostasis, and reveals the previously unreported involvement of ILK not only in epidermal differentiation and barrier formation, but also in melanocyte genesis and function.
    PLoS ONE 05/2012; 7(5):e36704. DOI:10.1371/journal.pone.0036704 · 3.23 Impact Factor
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