Discipline: Biological Sciences
Subcategory: Cell and Molecular Biology
Matilde Miranda - University of California, Los Angeles
Co-Author(s): William Lowry, University of California Los Angeles, Los Angeles, CA
Hair follicle stem cells (HFSCs) cycle through periods of growth (anagen) and rest (telogen). HFSCs located in the stem cell-containing compartment called the bulge have been shown to be the cells responsible for growing hair shafts de novo, contributing to wound healing, and are the cells of origin for squamous cell carcinoma (SCC). Previous data from our lab showed that HFSC quiescence is a tumor suppressor mechanism whereby the initiation of SCC by HFSCs requires active hair cycling. Therefore, we are exploring whether regulation of HFSC activation and the hair cycle can influence SCC initiation. Several lines of evidence point to a role for G-protein-coupled receptor(GPCR) signaling in regulation of the hair cycle (androgens, Lgr5). GPCR signaling typically leads to activation of adenyl cyclase which regulates levels of cAMP, and ultimately leading to CREB (cAMP response element-binding protein) activation — a signaling dependent transcription factor. Inhibition of Creb has been shown to block SCC initiation in the skin. Therefore, we hypothesized that classical GPCR signaling/Creb could play a role in regulating HFSC quiescence and activation, and thereby affect the onset of SCC. There have been reports of particular GPCRs involved in promoting telogen-to-anagen transition, but it is unclear if this is ultimately due to activation of Creb targets. Furthermore, whether GPCR/Creb signaling interacts with well-established signaling pathways (such as BMP, TGFβ, Wnt) in HFSC activation is unknown. We are taking advantage of various small molecules that act on a range of steps in GPCR/Creb signaling to determine how HFSC activation is regulated by these pathways. We first looked at Creb activation across the hair cycle by immunostaining for phospho-Creb and found increased Creb activity in the bulge upon anagen entry. Going forward, we will determine how GPCR/Creb signaling regulates HFSC activation in the contexts of aging and tumorigenesis. We then expect to identify transcriptional targets of Creb signaling involved in HFSC activation. Extensive characterization of GPCR/CREB signaling in follicular homeostasis will therefore allow for novel methods to not only regulate the hair cycle but also provide a mechanism by which CREB is able to promote or prevent SCC.
References: White, A. C. et al. Defining the origins of Ras/p53-mediated squamous cell carcinoma. Proc. Natl Acad. Sci. USA 108, 7425-7430 (2011). White, A.C. et al. Stem cell quiescence acts as a tumour suppressor in squamous tumours. Nat. Cell Biol. 16, 99-107 (2014). Rozenberg, J. et al. Inhibition of CREB function in mouse epidermis reduces papilloma formation. Mol. Cancer Res. 7, 654-664 (2009). Li, N. et al. Exogenous R-Spondin1 Induces Precocious Telogen-to-Anagen Transition in Mouse Hair Follicles. Int. J. Mol. Sci. 582, 17.4 (2016). Smith, A.A. et al. Activating hair follicle stem cells via R-spondin2 to stimulate hair growth. J. Invest. Dermatol. (2016).
Funder Acknowledgement(s): This work is made possible by the UCLA Broad Stem Cell Research Center and Gaba fund. I am also extremely grateful for being funded by NSF-GRFP and NSF Bridges to the Doctorate.
Faculty Advisor: William Lowry, firstname.lastname@example.org
Role: Currently, I am the only student involved in this project and the primary lead for the experiments, analysis, and presentation of data. This is my main project for the remainder of my graduate career in the Lowry lab. In addition, I consult with my mentor for intellectual direction and experimental ideas.