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EGFR and hair shaft differentiation

ABSTRACT: EGFR signaling controls skin development and homeostasis in mice and humans and its deficiency causes severe skin inflammation, which might affect epidermal stem cell behaviour. Here, we describe the inflammation-independent effects of EGFR-deficiency during skin morphogenesis and in adult HFSCs. Expression and alternative splicing analysis of RNAseq data from interfollicular epidermis and outer root sheath indicate that EGFR controls genes involved in epidermal differentiation, but also in centrosome function, DNA damage, cell cycle and apoptosis. Genetic experiments employing p53-deletion in EGFR–deficient epidermis reveal that EGFR signalling exhibits p53-dependent functions in proliferative epidermal compartments, as well as p53–independent functions in differentiated hair shaft keratinocytes. Loss of EGFR leads to absence of Lef1 protein specifically in the innermost epithelial hair layers, resulting in disorganization of medulla cells. Thus, our results uncover important spatial and temporal features of cell-autonomous EGFR functions in the epidermis.

ORGANISM(S): Mus musculus

PROVIDER: GSE128436 | GEO | 2019/07/23

REPOSITORIES: GEO

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Project description:Cell fates are defined by specific transcriptional program. Previously, we developed a unique stem cell regeneration mouse model, in which transcriptional program for ectoderm organs such as tooth and skin is switched. Genomic deletion of one subunit of Mediator complex, Med1, resulted in defective enamel regeneration, in which dental stem cells were inhibited from undergoing transcriptional program for dental fate. In stead, they exerted skin program for both hair and epidermis, and post-natally regenerate ectopic hairs in the incisors. Here, we report that Med1 also modulates epidermal and hair cell fates in the skin. Med1 ablation further enhanced epidermal and sebocyte fates, and accelerated injury induced epidermal regeneration. However, it blunted hair fate resulting in hair loss in the skin. Ablation of Med1 increased the number of isthmus stem cells and epidermal stem cells, which regenerate epidermis during cutaneous wound healing process. Med1 deficiency also constitutively activated these stem cells and increased their proliferation. Microarray profiling indicated that Med1 deletion causes activation of β-catenin and suppression of TGFβ signaling. Med1 deficiency induced the expression of β-catenin target genes to control cell fate and proliferation. It also decreased TGFβ expression in interfollicular epidermis. Med1 deficiency increased the proliferation and migration of epidermal cells, and induced nuclear translocation of β-catenin, and decreased TGFβ1 expression in vitro. Our finding together with previous observations demonstrated that Med1 governs ectoderm cell fate in both tooth and skin. Med1 ablation blunts hair fate but induces epidermal and sebocyte cell fates to accelerated injury induced epidermal regeneration in the skin. Accelerated regeneration is derived from constitutive activation of epidermal stem cells accompanied with increased proliferation and migration of their progeny by balancing of β-catenin induced growth promoting and TGFβ mediated growth inhibitory activities in the skin.

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EGFR and hair shaft differentiation

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