Melanocyte stem cells (McSCs) sustain a healthy population of melanocytes throughout life. Understanding their behavior and regulation is relevant to disorders resulting from melanocyte loss such as post inflammatory hypopigmentation, vitiligo, and hair graying, as well as to the biology of melanoma. Currently, little is known about the cellular and molecular mechanisms that govern McSCs. The goal of this grant is to understand the function of Wnt signaling and its regulation in McSCs residing in the hair follicle. McSCs are coordinately activated with follicular epithelial stem cells (EpSCs) during the cyclical regeneration of the hair follicle. They provide differentiated melanocytes to the hair bulb for the production of hair pigment. We discovered that McSCs activate Wnt signaling following Wnt ligand secretion from adjacent EpSCs at the onset of anagen. By transgenically deleting or activating 2-catenin, a key mediator of Wnt signaling in McSCs, we have shown that Wnt signaling is crucial for McSC differentiation. We hypothesize that Wnt signaling is required for McSC differentiation and that EpSCs coordinately regulate Wnt signaling in McSCs and EpSCs themselves during the hair follicle cycle. To address this hypothesis, we will pursue the following specific aims.
In Aim1, we will inhibit Wnt signaling in McSCs by expressing either a secreted inhibitor of Wnt signaling, Dkk1, or a dominant- negative form of a nuclear mediator of Wnt signaling, Lef1, in melanocytes. We will examine how this influences their ability to give rise to functional melanocytes during the hair cycle.
In Aim2, to determine if Wnt ligand(s) secreted by EpSCs can activate Wnt signaling in neighboring McSCs and promote their differentiation, we will delete the Wntless gene, which is necessary for Wnt ligand secretion, in follicular EpSCs or force expression of a Wnt ligand by EpSCs, using genetic mouse models.
In Aim3, we will test if Wnt inhibitors can promote McSC maintenance during aging, a process known to result in McSC exhaustion and loss following their aberrant differentiation. Specifically, we will utilize transgenic mouse models to overexpress either Dkk1 or a dominant-negative form of Lef1 in McSCs to examine if this promotes the maintenance of undifferentiated McSCs during aging. We will also test if Wnt inhibition can reverse McSC differentiation, a process that presages their ensuing loss. Our study will provide us with a novel understanding of the molecular mechanisms regulating McSCs and how melanocyte behavior is coordinated with hair regeneration, providing a scientific foundation for understanding diseases in which melanocytes are either inappropriately lost such as hair graying and vitiligo or undergo uncontrolled cell growth as in melanoma.

Public Health Relevance

The function and regulation of Wnt signaling in melanocyte stem cells is currently unknown. We propose to investigate the hypothesis that Wnt signaling regulates the maintenance and differentiation of melanocyte stem cells and that follicular epithelial stem cells are critical mediators of melanocyte Wnt signaling. This study will advance our understanding of the molecular signals that regulate melanocyte stem cells and will ultimately help development of novel strategies to treat diseases in which melanocytes are either inappropriately lost such as hair graying and vitiligo or undergo uncontrolled cell growth as in melanoma.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AR059768-04
Application #
8707375
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Tseng, Hung H
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
New York University
Department
Dermatology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10016
Gay, Denise; Kwon, Ohsang; Zhang, Zhikun et al. (2013) Fgf9 from dermal ýýýý T cells induces hair follicle neogenesis after wounding. Nat Med 19:916-23
Myung, Peggy S; Takeo, Makoto; Ito, Mayumi et al. (2013) Epithelial Wnt ligand secretion is required for adult hair follicle growth and regeneration. J Invest Dermatol 133:31-41
Takeo, Makoto; Chou, Wei Chin; Sun, Qi et al. (2013) Wnt activation in nail epithelium couples nail growth to digit regeneration. Nature 499:228-32
Chou, Wei Chin; Takeo, Makoto; Rabbani, Piul et al. (2013) Direct migration of follicular melanocyte stem cells to the epidermis after wounding or UVB irradiation is dependent on Mc1r signaling. Nat Med 19:924-9
Myung, Peggy; Ito, Mayumi (2012) Dissecting the bulge in hair regeneration. J Clin Invest 122:448-54