The long-term objective of this research is to gain a better understanding of the regulation of skin development. The goal of this project is to elucidate the function of Foxn1, a member of the winged- helix/forkhead family of transcription factors. In rodents, the loss of Foxn1 function results in the nude phenotype, which is characterized by the abnormal morphogenesis of the skin, thymus, mammary gland, and nails. Based on our work to date, we have developed the following model of Foxn1 function. In the skin, epithelial cells induce Foxn1 as they lose the ability to multiply and initiate terminal differentiation. In a site- dependent manner, Foxn1 then promotes up to three developmental processes: the differentiation of its host cells, the melanization of its host cells by melanocytes, and the growth of its surrounding host epithelium. To regulate these processes, Foxn1 activates intercellular signaling systems, thereby inducing epithelial cells to cooperate with each other and pigment cells. According to this model therefore, Foxn1 acts as a regulatory nexus, coordinating the growth, differentiation, and pigmentation of cutaneous tissues. To explain how this Foxn1 nexus works, we have developed the following hypothesis: that Foxn1 organizes cells into cooperative units by activating two types of extracellular signals - diffusible signals, which are responsible for Foxn1's long-range actions (e.g., the induction of cell proliferation and the recruitment of melanocytes to epithelial cells), and cell-bound signals, which are responsible for Foxn1's short-range actions (e.g., the flagging of epithelial cells for pigmentation and the locking of pigmentary connections into place). To test this hypothesis and the underlying model, the downstream effectors of Foxn1 will be elucidated.
The specific aims of the project are as follows: 1) to isolate and characterize Foxn1 effectors, 2) to determine the significance of the effectors to the Foxn1 pathway and skin, and 3) to dissect the molecular mechanisms by which Foxn1 regulates its effectors. In humans, FOXN1 is conserved in sequence and function, suggesting it employs a conserved set of downstream effectors. Thus, by identifying Foxn1 effectors, the project should provide insight into disorders associated with the abnormal growth, differentiation, or activity of melanocytes and epithelial cells.

Public Health Relevance

This project will elucidate fundamental mechanisms by which the skin develops and regenerates its protective epithelial traits. Specifically, the work will delineate a genetic pathway that drives and coordinates the growth, differentiation, and pigmentation of the skin's external structures. In the short term, the project will explain in part how the skin produces and assembles its barrier to the environment, which provides essential protection against pathogens, hazardous chemicals, ultraviolet light, and water loss. Over the long term, the project will provide insight into how skin may be clinically generated or manipulated, thus facilitating methods for the replacement or repair of damaged and diseased skin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR045284-14
Application #
8280156
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
1998-09-30
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
14
Fiscal Year
2012
Total Cost
$341,075
Indirect Cost
$127,235
Name
Suny Downstate Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
040796328
City
Brooklyn
State
NY
Country
United States
Zip Code
11203
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
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
Antonini, Dario; Rossi, Barbara; Han, Rong et al. (2006) An autoregulatory loop directs the tissue-specific expression of p63 through a long-range evolutionarily conserved enhancer. Mol Cell Biol 26:3308-18
Sharov, Andrei A; Weiner, Lorin; Sharova, Tatyana Y et al. (2003) Noggin overexpression inhibits eyelid opening by altering epidermal apoptosis and differentiation. EMBO J 22:2992-3003
Han, Rong; Baden, Howard P; Brissette, Janice L et al. (2002) Redefining the skin's pigmentary system with a novel tyrosinase assay. Pigment Cell Res 15:290-7

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