Maintenance of specialized epidermis requires signals from the underlying mesenchyme; however, specific pathways involved remain to be identified. By recombining cells from ventral skin of the K14-PTHrP transgenic mice with those from wild-type, we show that transgenic stroma is sufficient to reprogram wild-type keratinocytes into nipple-like epidermis. To identify candidate nipple-specific signaling factors, we compared gene expression signatures of sorted Pdgfrα-positive ventral K14-PTHrP and wild-type fibroblasts, identifying differentially-expressed transcripts of the WNT, HGF, TGFβ, IGF, BMP, FGF and estrogen signaling. Considering that some of the growth factor pathways are targets for estrogen regulation, we examined the hormone's upstream role in maintaining the nipple. Ablation of estrogen signaling by ovariectomy produced nipples with abnormally thin epidermis, and we identified TGFβ as a negatively regulated target of estrogen signaling. Estrogen treatment represses Tgfβ1 at the transcript and protein levels in K14-PTHrP fibroblasts in vitro, while ovariectomy increased Tgfβ1 in K14-PTHrP ventral skin. Moreover, ectopic delivery of Tgfβ1 protein into nipple connective tissue reduced epidermal proliferation. Taken together, specialized nipple epidermis is maintained by estrogen-induced repression of TGFβ signaling in the local fibroblasts.
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