The goal of this research is to gain a better understanding of the regulation of skin development. As self-renewing structures, the epidermis and hair follicles require a balance between keratinocyte cell division and terminal differentiation for their formation and maintenance. To gain insight into this process, the applicants are studying the function of Whn (Winged-helix nude), the product of the mouse nude locus and a putative member of the winged-helix/forkhead family of transcription factors. Loss-of-function mutations in whn result in the nude phenotype, which is characterized by the failure to produce visible hair, the abnormal formation of the epidermis, and the absence of a thymus. Based on their previous studies, the applicants have constructed a model to explain Whn's role in skin morphogenesis. They find that whn expression is induced, as keratinocytes arrest growth and initiate terminal differentiation. They postulate that Whn: 1) promotes the transition from proliferation to differentiation by activating genes associated with the differentiation program; and 2) induces differentiating cells to secrete growth factors. These growth factors then stimulate neighboring keratinocytes, which lack the Whn protein, to proliferate. As a result of this paracrine mechanism, a differentiating keratinocyte is replaced as it leaves the proliferative compartment, and the balance between multiplying and differentiating cells is maintained.
The aim of this proposal is to test this model and provide a basic framework for the elucidation of Whn's mechanism of action. To assess Whn's direct and paracrine effects, transgenic mice will be generated in which Whn expression is specifically targeted to either proliferating or differentiating keratinocytes. Since the investigators have acquired preliminary evidence that Whn stimulates the expression of transforming growth factor-a (TGF-a), the ability of Whn to bind to the TGF-a promoter and activate transcription will be evaluated. Lastly, they and others have isolated the human homolog of whn, and find that the human and murine Whn proteins are 85 percent identical. As a first step in the characterization of this homolog, the Whn expression pattern will be examined in normal and diseased human skin. Given the pleiotropic effects of murine whn, the human homolog they believe could play a role in diseases associated with hyperproliferation, hair loss, or aberrant differentiation.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Moshell, Alan N
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Kashiwagi, Mariko; Hosoi, Junichi; Lai, Jen-Feng et al. (2017) Direct control of regulatory T cells by keratinocytes. Nat Immunol 18:334-343
Antonini, Dario; Sirico, Anna; Aberdam, Edith et al. (2015) A composite enhancer regulates p63 gene expression in epidermal morphogenesis and in keratinocyte differentiation by multiple mechanisms. Nucleic Acids Res 43:862-74
Weiner, Lorin; Fu, Wenyu; Chirico, William J et al. (2014) Skin as a living coloring book: how epithelial cells create patterns of pigmentation. Pigment Cell Melanoma Res 27:1014-31
Han, Rong; Beppu, Hideyuki; Lee, Yun-Kyoung et al. (2012) A pair of transmembrane receptors essential for the retention and pigmentation of hair. Genesis 50:783-800
Mandinova, Anna; Kolev, Vihren; Neel, Victor et al. (2009) A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans. J Clin Invest 119:3127-37
Amorosi, S; D'Armiento, M; Calcagno, G et al. (2008) FOXN1 homozygous mutation associated with anencephaly and severe neural tube defect in human athymic Nude/SCID fetus. Clin Genet 73:380-4
Kim, Chun; Sano, Yasuyo; Todorova, Kristina et al. (2008) The kinase p38 alpha serves cell type-specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression. Nat Immunol 9:1019-27
Zuo, Ying; Zhuang, Debbie Z; Han, Rong et al. (2008) ABCA12 maintains the epidermal lipid permeability barrier by facilitating formation of ceramide linoleic esters. J Biol Chem 283:36624-35
Weiner, Lorin; Han, Rong; Scicchitano, Bianca M et al. (2007) Dedicated epithelial recipient cells determine pigmentation patterns. Cell 130:932-42
Li, Jian; Baxter, Ruth M; Weiner, Lorin et al. (2007) Foxn1 promotes keratinocyte differentiation by regulating the activity of protein kinase C. Differentiation 75:694-701

Showing the most recent 10 out of 14 publications