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Epidermal overexpression of ∆NLef1 leads to deregulation of epidermal stem cell fate

ABSTRACT: In adult K14ΔNLef1 mouse, the overexpression of ∆NLef1, a B-catenin dominat negative, in basal keratinocytes leads to the conversion of hair follicles into multilayered epithelial cysts and ectopic sebaceous gland. To uncover in vivo changes in gene expression associated to ΔNLef1 activity, we compared the expression profiles of basal keratinocytes (Itga6+) and bulge stem cells (cd34+/itga6+) in wild type and K14ΔNLef1 transgenic mice. Cells were collected from 9.5 week old mice, when the hair follicle are in the resting (telogen) phase of the hair growth cycle. At this stage the ΔNLef1 phenotype is not yet evident enabling us to detect early molecular events.

ORGANISM(S): Mus musculus

PROVIDER: GSE118073 | GEO | 2019/03/08

REPOSITORIES: GEO

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Project description:Hair follicle formation depends on reciprocal epidermal-dermal interactions and occurs during skin development, but not in adult life. This suggests that the properties of dermal fibroblasts change during postnatal development. To examine this, we used a PdgfraEGFP mouse line to isolate GFP-positive fibroblasts from neonatal skin, adult telogen and anagen skin and adult skin in which ectopic hair follicles had been induced (EF skin) by transgenic epidermal activation of beta-catenin. We also isolated epidermal cells from each mouse. The gene expression profile of EF epidermis was most similar to that of anagen epidermis, consistent with activation of beta-catenin signalling. In contrast, adult dermis with ectopic hair follicles more closely resembled neonatal dermis than adult telogen or anagen dermis. In particular, genes associated with mitosis were upregulated and extracellular matrix-associated genes were downregulated in neonatal and EF fibroblasts. We confirmed that sustained epidermal beta-catenin activation stimulated fibroblasts to proliferate to reach the high cell density of neonatal skin. In addition, the extracellular matrix was comprehensively remodelled, with mature collagen being replaced by collagen subtypes normally present only in developing skin. The changes in proliferation and extracellular matrix composition originated from a specific subpopulation of fibroblasts located beneath the sebaceous gland. Our results show that adult dermis is an unexpectedly plastic tissue that can be reprogrammed to acquire the molecular, cellular and structural characteristics of neonatal dermis in response to cues from the overlying epidermis. We have isolated the following populations of cells from mouse back skin by flow cytometry: 1A) GFP+ WT neonatal dermal fibroblasts, 1B) ItgA6+ WT neonatal epidermal keratinocytes, 2A) GFP+ WT telogen dermal fibroblasts, 2B) ItgA6+ WT telogen epidermal keratinocytes, 3A) GFP+ D2 transient activation (anagen) dermal fibroblasts, 3B) ItgA6+ D2 transient activation (anagen) epidermal keratinocytes, 4A) GFP+ D2 sustained activation (ectopic follicles) dermal fibroblasts, 4B) ItgA6+ D2 sustained activation (ectopic follicles) epidermal keratinocytes

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Epidermal overexpression of ∆NLef1 leads to deregulation of epidermal stem cell fate

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