Summary It is currently unclear whether tissue changes surrounding multifocal epithelial tumors are a cause or consequence of cancer. Here, we provide evidence that loss of mesenchymal Notch/CSL signaling causes tissue alterations, including stromal atrophy and inflammation, which precede and are potent triggers for epithelial tumors. Mice carrying a mesenchymal-specific deletion of CSL/RBP-Jκ, a key Notch effector, exhibit spontaneous multifocal keratinocyte tumors that develop after dermal atrophy and inflammation. CSL-deficient dermal fibroblasts promote increased tumor cell proliferation through up-regulation of c-Jun and c-Fos expression and consequently higher levels of diffusible growth factors, inflammatory cytokines, and matrix remodeling enzymes. In human skin samples, stromal fields adjacent to cutaneous squamous cell carcinomas and multifocal premalignant actinic keratosis lesions exhibit decreased Notch/CSL signaling and associated molecular changes. Importantly, these changes in gene expression are also induced by UVA, a known environmental cause of cutaneous field cancerization and skin cancer.

Epithelial–mesenchymal interactions are key to skin morphogenesis and homeostasis. We report that maintenance of the hair follicle keratinocyte cell fate is defective in mice with mesenchymal deletion of the CSL/RBP-Jκ gene, the effector of “canonical” Notch signaling. Hair follicle reconstitution assays demonstrate that this can be attributed to an intrinsic defect of dermal papilla cells. Similar consequences on hair follicle differentiation result from deletion of Wnt5a, a specific dermal papilla signature gene that we found to be under direct Notch/CSL control in these cells. Functional rescue experiments establish Wnt5a as an essential downstream mediator of Notch–CSL signaling, impinging on expression in the keratinocyte compartment of FoxN1, a gene with a key hair follicle regulatory function. Thus, Notch/CSL signaling plays a unique function in control of hair follicle differentiation by the underlying mesenchyme, with Wnt5a signaling and FoxN1 as mediators.

The results show that rats exhibiting a similar degree of blood pressure elevation, as the result of different mechanisms, feature a comparable increase in Cx43 gene expression, which was observed in the aortic but not in the cardiac muscle. These data suggest that localized mechanical forces induced by hypertension are major tissue-specific regulators of Cx43 expression.

Energy balance exerts a critical influence on reproduction via changes in the circulating levels of hormones such as insulin. This modulation of the neuroendocrine reproductive axis ultimately involves variations in the activity of hypothalamic neurons expressing GnRH. Here we studied the effects of insulin in primary hypothalamic cell cultures as well as a GnRH neuronal cell line that we generated by conditional immortalization of adult hypothalamic neurons. These cells, which represent the first successful conditional immortalization of GnRH neurons, retain many of their mature phenotypic characteristics. In addition, we show that they express the insulin receptor. Consistently, their stimulation with insulin activates both the phosphatidylinositol 3-kinase and the Erk1/2 MAPK signaling pathways and stimulates a rapid increase in the expression of c-fos, demonstrating their responsiveness to this hormone. Further work performed in parallel in immortalized GnRH-expressing cells and primary neuronal cultures containing non-GnRH-expressing neurons shows that insulin induces the expression of GnRH in both models. In primary cultures, inhibition of the Erk1/2 pathway abolishes the stimulation of GnRH expression by insulin, whereas blockade of the phosphatidylinositol 3-kinase pathway has no effect. In conclusion, these data strongly suggest that GnRH neurons are directly sensitive to insulin and implicate for the first time the MAPK Erk1/2 signaling pathway in the central effects of insulin on the neuroendocrine reproductive axis.

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