Description of Research Expertise:
Epithelial stem cells and regeneration; development of hair follicles, mammary glands, taste papillae and teeth; regeneration and neogenesis of hair follicles and teeth; hair follicle, mammary gland and dental stem cells; skin and mammary gland tumorigenesis; microRNA functions in embryonic and postnatal skin and mammary glands; skin epigenetics; functions of histone deacetylases in skin and hair follicle development and renewal.
Key words: hair, stem cells, regeneration, skin, tooth, mammary gland, mouse, Wnt, Bmp, beta-catenin, Dicer, miRNA, histone deaceylase, HDAC, chromatin.
Description of Research
Our research is focused on understanding cell-cell signaling mechanisms controlling development, stem cell function and regeneration of the epidermis and organs such as hair follicles, mammary glands, taste papillae and teeth that arise from embryonic ectoderm (ectodermal appendages). We have shown that Wnt/beta-catenin signaling is required for initiating the formation of hair follicles, mammary glands and taste papillae from multipotent cells in the embryonic surface ectoderm, and plays key roles in regulating the functions of adult epithelial stem cells. We are currently using genetic approaches to determine how Wnt signaling is regulated and patterned within the skin, and are utilizing activation of this pathway in strategies for organ regeneration. We are using genetic approaches to identify Wnt ligands and receptors required for appendage development, and to investigate the roles played by non-beta-catenin mediated Wnt signaling in the skin. We are also interested in epigenetic mechanisms controlling development, differentiation, regeneration and tumorigenesis. Currently, we are investigating the mechanisms by which histone deacetylases control self-renewal and differentiation of skin stem cells, and are probing the roles of specific HDAC family members in skin tumorigenesis.
1. Dissection of mechanisms controlling patterning of ectodermal appendages using live imaging and genetic approaches
2. Epigenetic mechanisms regulating skin development, stem cells and cancer
3. Identification of Wnt ligands and inhibitors regulating skin stem cell functions
4. Modulation of skin regeneration by Wnt inhibitors
Donna Brennan-Crispi, Ph.D., Post-doctoral Fellow
Mingang Xu, Ph.D., Research Associate
Xuming Zhu, Post-doctoral fellow
DJ Moran, PhD thesis student
Kate Szigety, MD PhD thesis student
Ana Boncompagni, Undergraduate Student
Max Frankfurter, Undergraduate student
Troy Thayer, Dental student
Henry Vanderfin, Dental student
Hana Soon, Dental student
Xu Mingang, Horrell Jeremy, Snitow Melinda, Cui Jiawei, Gochnauer Heather, Syrett Camille M, Kallish Staci, Seykora John T, Liu Fei, Gaillard Dany, Katz Jonathan P, Kaestner Klaus H, Levin Brooke, Mansfield Corinne, Douglas Jennifer E, Cowart Beverly J, Tordoff Michael, Liu Fang, Zhu Xuming, Barlow Linda A, Rubin Adam I, McGrath John A, Morrisey Edward E, Chu Emily Y, Millar Sarah E: WNT10A mutation causes ectodermal dysplasia by impairing progenitor cell proliferation and KLF4-mediated differentiation. Nature communications 8 : 15397,2017.
Choi Yeon Sook, Zhang Yuhang, Xu Mingang, Yang Yongguang, Ito Mayumi, Peng Tien, Cui Zheng, Nagy Andras, Hadjantonakis Anna-Katerina, Lang Richard A, Cotsarelis George, Andl Thomas, Morrisey Edward E, Millar Sarah E: Distinct functions for Wnt/β-catenin in hair follicle stem cell proliferation and survival and interfollicular epidermal homeostasis. Cell stem cell 13 (6): 720-33,2013.
Teta Monica, Choi Yeon Sook, Okegbe Tishina, Wong Gabrielle, Tam Oliver H, Chong Mark M W, Seykora John T, Nagy Andras, Littman Dan R, Andl Thomas, Millar Sarah E: Inducible deletion of epidermal Dicer and Drosha reveals multiple functions for miRNAs in postnatal skin. Development (Cambridge, England) 139 (8): 1405-16,2012.
LeBoeuf Matthew, Terrell Anne, Trivedi Sohum, Sinha Satrajit, Epstein Jonathan A, Olson Eric N, Morrisey Edward E, Millar Sarah E: Hdac1 and Hdac2 act redundantly to control p63 and p53 functions in epidermal progenitor cells. Developmental Cell 19 (6): 807-18,2010.
Liu F, Dangaria S, Andl T, Zhang Y, Wright A C, Damek-Poprawa M, Piccolo S, Nagy A, Taketo M M, Diekwisch T G H, Akintoye S O, Millar S E: beta-Catenin initiates tooth neogenesis in adult rodent incisors. Journal of Dental Research 89 (9): 909-14,2010.
Zhang Y, Tomann P, Andl T, Gallant NM, Huelsken J, Jerchow B, Birchmeier W, Paus R, Piccolo S, Mikkola ML, Morrisey EE, Overbeek P, Scheidereit C, Millar SE*, Schmidt-Ullrich R*. [*Joint last and corresponding authors.]: Reciprocal requirements for Eda/Edar/NF-kappa B and Wnt/b-catenin signaling pathways in hair follicle induction. Developmental Cell 17, 49-61 : 2009.
Zhang, Y., Andl, T., Yang, S.H., Teta, M., Liu, F., Seykora, J.T., Tobias, J.W., Piccolo, S., Schmidt-Ullrich, R., Nagy, A., Taketo, M.M., Dlugosz, A.A., Millar, S.E.: Activation of beta-catenin signaling programs embryonic epidermis to hair follicle fate. Development 135 : 2161-72,2008.
Liu, F., Thirumangalathu, S., Gallant, N. M., Yang, S. H., Stoick-Cooper, C. L., Reddy, S. T., Andl, T., Taketo, M. M., Dlugosz, A. A., Moon, R. T., Barlow, L. A., Millar, S. E.: Wnt-beta-catenin signaling initiates taste papilla development. Nat Genet. 39 : 106-12,2007.
Andl, T., Murchison, E. P., Liu, F., Zhang, Y., Yunta-Gonzalez, M., Tobias, J. W., Andl, C, D., Seykora, J. T., Hannon, G. J., Millar, S. E.: The miRNA processing enzyme Dicer is essential for the morphogenesis and maintenance of hair follicles Current Biology 6 : 1041-9,2006.
Andl, T., Reddy S. T., Gaddapara, T. & Millar, S. E.: WNT signals are required for the initiation of hair follicle development. Developmental Cell 2 : 643-653,2002.
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