The goal of this project is to identify the molecular partners of Foxn1 and to elucidate their contributions to skin development. Foxn1 is a transcription factor containing a winged-helix DNA-binding domain and a negatively charged transactivation domain. In rodents, the loss of Foxn1 function results in the nude phenotype, which is characterized by the abnormal morphogenesis of the skin, thymus, and mammary gland. To promote skin development, Foxn1 performs an unusual function, which was delineated by us in previous studies. Foxn1 becomes activated as epithelial cells initiate terminal differentiation in the epidermis and hair follicles. In a site-dependent manner, Foxn1 then plays up to three roles: 1) it allows its host cell to differentiate properly, 2) it stimulates the host cell's neighbors to divide, and 3) it recruits melanocytes to the host cell, thus identifying its host as a target for pigmentation. Through this combination of actions, Foxn1 enables groups of cells to work in concert and drives epithelial growth, differentiation, and pigmentation forward together. Presumably, Foxn1 itself works in concert with other factors, which provide it with information, determine its level of activity, direct it to specific targets, or function side-by-side with it in synergistic fashion. Undoubtedly, Foxn1 requires these partners for efficacy, making the partners of Foxn1 essential to the morphogenesis of the skin and other organs. During the course of this project, we will identify the partners of Foxn1 using two approaches, one genetic, the other biochemical. In the genetic approach, we will screen for mutations that modulate the activity or output of Foxn1. The screen will employ a novel model system, which we have developed for the study. In the biochemical approach, we will purify Foxn1 protein complexes from keratinocytes and dissect the individual components. Once partners are identified, we will determine how they contribute to the actions of Foxn1 and the morphogenesis of the skin. In humans, FOXN1 is conserved in sequence and function, suggesting a like conservation of partners. Accordingly, by elucidating the partnerships of Foxn1, the project should provide insight into the development of normal and diseased human skin, most especially, the disorders marked by the aberrant proliferation, differentiation, or pigmentation of epithelial cells. Project Narrative: This project will elucidate fundamental mechanisms by which the skin develops and regenerates its protective epithelial traits. Specifically, the work will delineate a genetic network 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 #
5R01AR055218-05
Application #
8225398
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
2008-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$333,495
Indirect Cost
$124,407
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
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
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