Like other organs, developing hair follicles arise via a precisely-orchestrated series of secreted signals traveling between epithelial hair follicle progenitors and an adjacent mesenchymal condensate, which together ultimately generate a mature, hair-producing follicle. After birth, the follicle repeatedly cycles through periods of growth, regression, and rest, making it a unique model for studying organogenesis in postnatal life. Work from our lab and others has established that secreted Sonic hedgehog (Shh), which is produced by follicle epithelium and signals to both epithelial and mesenchymal follicle progenitors, is an indispensable regulator of embryonic hair follicle growth, but not differentiation. We have shown that the primary target for Shh in developing hair follicles is the epithelium, and that the proliferative response to Shh is mediated by the transcription factor GH2. We have also found that the Hedgehog (Hh) pathway is involved in the formation of oil-producing sebaceous glands, and that focal activation of Hh signaling is sufficient to drive epithelial bud development, a process previously shown to be controlled by Wnt signals. We hypothesize that epithelial Hh signaling can initiate epithelial bud formation in the absence of a mesenchymal signal, and that the Hh pathway normally drives cell proliferation during periods of active follicle growth after birth. In addition, we propose that Hh signaling has a crucial function in sebocyte development. To test these hypotheses, we have developed conditional mouse models that enable precise spatial and temporal control of Hh signaling activity. These models will be used to: 1) ascertain whether Hh signaling stimulates growth of follicle epithelium by acting directly on stem cells, their progeny, or both; 2) determine the precise function of Hh signaling in sebaceous gland development and maintenance; and 3) explore the mechanism by which ectopic, focal activation of Hh signaling leads to formation of epithelial buds. Given the widespread importance of Hh signaling in embryogenesis and cancer development, our findings in the hair follicle are likely to facilitate understanding of physiologic and pathologic Hh signaling in a variety of other organs.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ACTS (01))
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Baker, Carl
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Kumari, Archana; Ermilov, Alexandre N; Grachtchouk, Marina et al. (2017) Recovery of taste organs and sensory function after severe loss from Hedgehog/Smoothened inhibition with cancer drug sonidegib. Proc Natl Acad Sci U S A 114:E10369-E10378
Ermilov, Alexandre N; Kumari, Archana; Li, Libo et al. (2016) Maintenance of Taste Organs Is Strictly Dependent on Epithelial Hedgehog/GLI Signaling. PLoS Genet 12:e1006442
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Kumari, Archana; Ermilov, Alexandre N; Allen, Benjamin L et al. (2015) Hedgehog pathway blockade with the cancer drug LDE225 disrupts taste organs and taste sensation. J Neurophysiol 113:1034-40
Wong, Sunny Y; Dlugosz, Andrzej A (2014) Basal cell carcinoma, Hedgehog signaling, and targeted therapeutics: the long and winding road. J Invest Dermatol 134:E18-22
Liu, Hong Xiang; Ermilov, Alexandre; Grachtchouk, Marina et al. (2013) Multiple Shh signaling centers participate in fungiform papilla and taste bud formation and maintenance. Dev Biol 382:82-97
Veniaminova, Natalia A; Vagnozzi, Alicia N; Kopinke, Daniel et al. (2013) Keratin 79 identifies a novel population of migratory epithelial cells that initiates hair canal morphogenesis and regeneration. Development 140:4870-80

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