Our global objective is to develop a molecular understanding of how epithelial stem cells undergo morphogenesis, homeostasis, and wound repair in mammalian skin and bring this research to a clinical setting. Our focus is on how skin stem cells utilize cytoskeletal connections to intercellular and cell substratum junctions to generate tissues. Knowledge of the proteins involved in coordinating actin filament (AF) cytoskeletal dynamics with adherens junctions (AJs) and elucidating how these connections are inversely coordinated with integrin-AF dynamics are key to understanding how self-renewing skin epithelium maintains and repairs its surface barrier and how a stem cell can give rise to a hair follicle (HF). Elucidating how microtubules (MTs) link to AJs is important for understanding how the stratified epidermis maintains a single layer of dividing cells, and how spindle polarity changes when stem cells are activated to produce HFs. A molecular understanding of these dynamics will be obtained by focusing on four cytoskeletal-junction linking proteins that surfaced as being key from our prior studies: -catenin, which coordinates and polarizes AF-AJ dynamics and suppresses AF-integrin dynamics;ACF7, which coordinates and polarizes MT-AF and Par3- mediated dynamics in a wound response;and Par3 and mInsc, whose polarization relies upon -catenin and 1 integrin, and which appear to be critical for orienting spindles in skin morphogenesis. Through biochemical and molecular approaches, we'll define and characterize the associated proteins that are involved in polarizing and remodeling cytoskeletal dynamics during skin morphogenesis and wound repair. Through mouse genetics and novel ShRNA strategies we've developed to rapidly knockdown genes in adult and embryonic skin, the functional significance of these proteins and their varied associations with other proteins will be ascertained. Finally, as the major players in these processes unfold, functional analyses will be combined with microarray data to define the underlying significance of global changes in AJ-cytoskeletal gene expression that occur concomitantly as stem cells receive external cues to remodel their AJ-cytoskeletal connections and initiate stratification and HF morphogenesis. Understanding how these cytoskeletal linkages are regulated in normal skin is a prerequisite to elucidating how defects in these processes lead to genetic disorders, including skin cancers. Past and present AR27883 research provides an excellent illustration of how molecular skin biology can help to generate new and improved tools for the diagnosis and treatment of human skin disease.

Public Health Relevance

Stem cells are natural units of tissue repair and homeostasis, and their versatility holds promise for tissue regeneration. This research focuses on deciphering how different tissue structures are derived from multipotent stem cells in the skin. Specifically, we focus on how stem cells within a single layer use cell-cell and cell substratum junctions to remodel their cytoskeleton to generate a stratified, differentiating epidermis or an invaginating hair follicle bud, and how this changes transiently in a wound response. This study is a fundamental prerequisite to understanding how aberrations in these basic properties go awry in skin cancers, including squamous cell carcinomas.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Development - 2 Study Section (DEV2)
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Baker, Carl
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Rockefeller University
Other Domestic Higher Education
New York
United States
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Schramek, Daniel; Sendoel, Ataman; Segal, Jeremy P et al. (2014) Direct in vivo RNAi screen unveils myosin IIa as a tumor suppressor of squamous cell carcinomas. Science 343:309-13
Antonellis, Patrick J; Pollock, Lana M; Chou, Shih-Wei et al. (2014) ACF7 is a hair-bundle antecedent, positioned to integrate cuticular plate actin and somatic tubulin. J Neurosci 34:305-12
Williams, Scott E; Ratliff, Lyndsay A; Postiglione, Maria Pia et al. (2014) Par3-mInsc and G?i3 cooperate to promote oriented epidermal cell divisions through LGN. Nat Cell Biol 16:758-69
Heller, Evan; Kumar, K Vijay; Grill, Stephan W et al. (2014) Forces generated by cell intercalation tow epidermal sheets in mammalian tissue morphogenesis. Dev Cell 28:617-32
Kulukian, Anita; Fuchs, Elaine (2013) Spindle orientation and epidermal morphogenesis. Philos Trans R Soc Lond B Biol Sci 368:20130016
Beronja, Slobodan; Janki, Peter; Heller, Evan et al. (2013) RNAi screens in mice identify physiological regulators of oncogenic growth. Nature 501:185-90
Williams, Scott E; Fuchs, Elaine (2013) Oriented divisions, fate decisions. Curr Opin Cell Biol 25:749-58
Wu, Xiaoyang; Shen, Qing-Tao; Oristian, Daniel S et al. (2011) Skin stem cells orchestrate directional migration by regulating microtubule-ACF7 connections through GSK3?. Cell 144:341-52
Ezratty, Ellen J; Stokes, Nicole; Chai, Sophia et al. (2011) A role for the primary cilium in Notch signaling and epidermal differentiation during skin development. Cell 145:1129-41
Devenport, Danelle; Oristian, Daniel; Heller, Evan et al. (2011) Mitotic internalization of planar cell polarity proteins preserves tissue polarity. Nat Cell Biol 13:893-902

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