Notch proteins regulate cell fate decisions and inhibit differentiation in many developmental systems. Notch1 signalling has been previously associated with tumorigenesis, but now one study indicates that this receptor protein might have the opposite role in skin cells.

The role of Notch signalling in mammalian skin is not well understood, although some in vitro studies have indicated that Notch induces differentiation in this tissue. In the March issue of Nature Genetics, Nicolas et al. perform tissue-specific gene targeting of Notch1 in the mouse epidermis and in the corneal epithelium. The authors made the surprising observation that disruption of Notch1 promoted epidermal and corneal hyperplasia. Within as little as 8 months of birth, these mice developed skin tumours in various parts of the body. A total of 95% of mice older than 12 months developed highly vascularized tumours that were histologically classified as basal-cell carcinomas. The mice were also more sensitive to chemical carcinogens.

These data were unexpected because, in other cell types, Notch1 is known to maintain proliferative cell populations in the undifferentiated state. In contrast with the common belief that Notch1 signalling is oncogenic, the findings of Nicolas et al. instead indicate that, in skin, Notch1 acts as a tumour suppressor. So what does Notch1 do in skin?

As basal-cell carcinomas are associated with activation of the Shh signalling pathway, Nicolas et al. looked to see if this pathway was activated in the tumours. They found that Notch1 deficiency in skin and primary keratinocytes resulted in increased and sustained expression of Gli2 — a transcriptional target of Shh. So, Notch1 might function to repress Gli2 expression, and thereby promote keratinocyte differentiation.

The authors also found that Notch1 inhibits β-catenin signalling in differentiating keratinocytes, as well as restricting its expression to cells of the basal-cell layer of the epidermis. Loss of Notch1, along with upregulation of β-catenin and Gli2, can therefore promote a pro-proliferative, anti-differentiation state in skin cells.