Adult epidermal Notch activity induces dermal accumulation of T cells and neural crest derivatives through upregulation of jagged 1

Abstract

SUMMARYNotch signalling regulates epidermal differentiation and tumour formation via non-cell autonomous mechanisms that are incompletely understood. This study shows that epidermal Notch activation via a 4-hydroxy-tamoxifen-inducible transgene caused epidermal thickening, focal detachment from the underlying dermis and hair clumping. In addition, there was dermal accumulation of T lymphocytes and stromal cells, some of which localised to the blisters at the epidermal-dermal boundary. The T cell infiltrate was responsible for hair clumping but not for other Notch phenotypes. Notch-induced stromal cells were heterogeneous, expressing markers of neural crest, melanocytes, smooth muscle and peripheral nerve. Although Slug1 expression was expanded in the epidermis, the stromal cells did not arise through epithelial-mesenchymal transition. Epidermal Notch activation resulted in upregulation of jagged 1 in both epidermis and dermis. When Notch was activated in the absence of epidermal jagged 1, jagged 1 was not upregulated in the dermis, and epidermal thickening, blister formation, accumulation of T cells and stromal cells were inhibited. Gene expression profiling revealed that epidermal Notch activation resulted in upregulation of several growth factors and cytokines, including TNF, the expression of which was dependent on epidermal jagged 1. We conclude that jagged 1 is a key mediator of non-cell autonomous Notch signalling in skin.

EctopicAtoh1expression drives Merkel cell production in embryonic, postnatal and adult epidermis

“…Interestingly, Rbpj deletion in the absence of Atoh1 transgene expression was itself sufficient to create a few ectopic K8+ cells, suggesting that the Notch pathway normally represses Atoh1 expression in at least a subset of epidermal cells. Variations in Notch pathway signaling occur during development and during different phases of the hair cycle, which might help to explain why Atoh1 induction produces more ectopic K8+ cells in embryos than in adult mice and in anagen versus telogen (Ambler and Watt, 2010;Favier et al, 2000;Powell et al, 1998). Furthermore, Notch1 is expressed by most Merkel cell carcinomas (MCCs) (Panelos et al, 2009), but whether Atoh1/Notch antagonism participates in MCC pathogenesis has not been investigated.…”

Modulating the stem cell niche for tissue regeneration

“…In the latter category, the Notch pathway stands out as being important in regulating stem cell function in many tissues. In the skin, it is well established that Notch signaling mediates distinct outcomes according to the level of pathway activation and acts both cell autonomously and non–cell autonomously by means of signaling between epidermal cells, fibroblasts and bone marrow–derived cells 43,44 (work by F.M.W. and colleagues).…”

Cutaneous Notch Signaling in Health and Disease

“…Additional evidence showing a link between the Notch pathway and inflammation is provided by the demonstration that ectopic Notch expression in basal epidermal cells results in serious abnormalities in the underlying dermis, characterized by an inflammatory infiltrate consisting of T cells (Ambler and Watt 2010). Thus, inflammation appears to be extremely sensitive to aberrations in epidermal Notch signaling, either with respect to signal strength or spatial localization.…”