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Development. 2017 Apr 15;144(8):1498-1509. doi: 10.1242/dev.141630. Epub 2017 Mar 13.

Estrogen modulates mesenchyme-epidermis interactions in the adult nipple.

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Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA.
Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, Center for Complex Biological Systems, University of California Irvine, Irvine, CA 92697, USA.
Department of Anatomy, School of Medicine, Kyungpook National University, Daegu, 41944, Korea.
Biomedical Research Institute, Kyungpook National University Hospital, Daegu, 41944, Korea.
Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA


Maintenance of specialized epidermis requires signals from the underlying mesenchyme; however, the specific pathways involved remain to be identified. By recombining cells from the ventral skin of the K14-PTHrP transgenic mice [which overexpress parathyroid hormone-related protein (PTHrP) in their developing epidermis and mammary glands] 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 that are involved in 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 upstream role of this hormone in maintaining the nipple. Ablation of estrogen signaling through 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 increases Tgfb1 levels in K14-PTHrP ventral skin. Moreover, ectopic delivery of Tgfβ1 protein into nipple connective tissue reduced epidermal proliferation. Taken together, these results show that specialized nipple epidermis is maintained by estrogen-induced repression of TGFβ signaling in the local fibroblasts.


Epidermis; Estrogen receptor α; Fibroblast; Nipple; TGFβ

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