Bi-compartmental communication contributes to the opposite proliferative behavior of Notch1-deficient hair follicle and epidermal keratinocytes

Abstract

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, Tgfβ 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. Tgfβ 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 Tgfβ receptors, consistent with paracrine Tgfβ 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.

Inducible deletion of epidermal Dicer and Drosha reveals multiple functions for miRNAs in postnatal skin

“…Notch signaling is downregulated and Tslp levels are elevated in Drosha and Dicer mutant skin Epidermal loss of Notch signaling produces phenotypes similar to those observed following miRNA depletion, including: severe abnormalities at later stages of HF morphogenesis; the ability of Drosha/Dicer-depleted and Notch-depleted bulge stem cells to contribute to the matrix, IRS and ORS; failure of HF maintenance; interfollicular epidermal hyperproliferation; and inflammation (Pan et al, 2004;Vauclair et al, 2005;Lee et al, 2007;Demehri et al, 2008;Demehri and Kopan, 2009). Consistent with this, levels of full-length (FL) Notch1 and Notch1 intracellular domain (NICD) were reduced by P17 in Dicer flEx22-23 and Drosha flEx9 mutants compared with control skin following induction from E18 (Fig.…”

Canonical Notch signaling in the developing lung is required for determination of arterial smooth muscle cells and selection of Clara versus ciliated cell fate

“…Overexpression of N1ICD (Guseh et al, 2009) exposed the tissue to non-physiological levels of Notch pathway activation in both the level and duration of the signal. Moreover, given that Hes1 can respond to other signaling pathways (Yoshiura et al, 2007), notably FGF (Nakayama et al, 2008), its activation might not depend on Notch in every cellular context (Lee et al, 2007). To look at which specific cell types require Notch activity during lung morphogenesis, and to begin to assign functions to specific receptors, we examined the role of Notch signaling in different compartments throughout lung development.…”

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

“…The Notch signaling pathway contributes to the maintenance of the follicular structure but not to cell fate selection during hair follicle morphogenesis (Pan et al, 2004). In addition, Notch signaling ensures an optimal proliferative environment in the matrix during first anagen by suppressing Tgfβ and activating Kit ligand (Lee et al, 2007).…”

“…Notch regulates keratinocyte proliferation, commitment and differentiation decisions in intact skin and in culture Lee et al, 2007;Pan et al, 2004;Rangarajan et al, 2001). In response to ligand binding, Notch receptors undergo sequential proteolysis by two enzymes (ADAM metalloprotease followed by γ-secretase) to release the active Notch intracellular domain fragment (NICD), which translocates into the nucleus, binds to Rbpj and nucleates the recruitment of a transcription-activating complex (Lubman et al, 2004).…”