The multi-layered epidermis provides an essential barrier against water loss, physical insults, and infection. Its proper function requires that architectural features be polarized along its entire apical to basal axis (superficial to deep layers). Contributing to the inherent tissue polarity of the epidermis are seven desmosomal cadherins, whose differentiation-dependent arrangement is thought to have functional significance that transcends intercellular adhesion. Indeed, our work during previous funding periods demonstrated that the cadherin desmoglein 1 (Dsg1), which is first expressed as cells commit to differentiate and transit into the suprabasal layers, acts as a scaffold that engages signaling mediators necessary for terminal differentiation. Its failure to be expressed or properly exported to the plasma membrane disrupts organismal homeostasis in patients with Severe dermatitis, Allergies and Metabolic wasting (SAM) syndrome, a syndrome we helped identify in 2013. We hypothesize that Dsg1 coordinates two interrelated but distinct functions required for epidermal morphogenesis: a biochemical program of differentiation, and cytoarchitectural changes required for stratification to form the multi-layered tissue. The resulting tissue provides a protective, dynamic barrier capable of sensing and responding to diverse mechanical and chemical stimuli. The specific objective of this proposal is to determine how Dsg1 mediates changes in tissue architecture and signaling necessary for morphogenesis. To fulfill this objective, we will use gain- and loss-of-function approaches in human 2- and 3D cultures, human patient tissue, and knockout mouse models to address three aims: 1) We will define the machinery that ensures the polarized distribution of Dsg1 in the epidermis, specifically, the extent to which Dsg1 is delivered to the correct position on the plasma membrane through a microtubule minus end-directed dynein-Tctex-Rab3D complex, requiring differentiation-dependent microtubule rearrangements. 2) We will elucidate how Dsg1 modulates the mechanosensitive cortical cytoskeleton to control a temporary drop in tension during formation of the first suprabasal cell layer, and then to concentrate tension in the granular layers later in morphogenesis to ensure proper tight junction structure. 3) We will determine how Dsg1 works with ErbB2 Interacting protein (Erbin) to promote epidermal differentiation by dampening Epidermal Growth Factor Receptor (EGFR) signaling, through disrupting protein complexes permissive for EGFR signaling and/or reducing EGFR mobility within the plasma membrane. These studies will reveal how Dsg1 coordinates cytoarchitectural changes and signaling machinery required for epidermal differentiation, stratification, and barrier formation, and will shed light on how interference with these functions contributes to inherited and acquired skin diseases and cancer.

Public Health Relevance

This project aims to understand how sticky molecules on the surface of skin cells facilitate the formation of a three-dimensional tissue to provide an essential barrier covering the surface of the body. The studies focus on new functions for these molecules, beyond their role in cell coherence, that control normal tissue development and disease processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR041836-26
Application #
9543323
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Cibotti, Ricardo
Project Start
1993-08-01
Project End
2022-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
26
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Vodo, D; O'Toole, E A; Malchin, N et al. (2018) Striate palmoplantar keratoderma resulting from a missense mutation in DSG1. Br J Dermatol 179:755-757
Polivka, Laura; Hadj-Rabia, Smail; Bal, Elodie et al. (2018) Epithelial barrier dysfunction in desmoglein-1 deficiency. J Allergy Clin Immunol 142:702-706.e7
Nekrasova, Oxana; Harmon, Robert M; Broussard, Joshua A et al. (2018) Desmosomal cadherin association with Tctex-1 and cortactin-Arp2/3 drives perijunctional actin polymerization to promote keratinocyte delamination. Nat Commun 9:1053
Mohamad, Janan; Sarig, Ofer; Godsel, Lisa M et al. (2018) Filaggrin 2 Deficiency Results in Abnormal Cell-Cell Adhesion in the Cornified Cell Layers and Causes Peeling Skin Syndrome Type A. J Invest Dermatol 138:1736-1743
Rübsam, Matthias; Broussard, Joshua A; Wickström, Sara A et al. (2018) Adherens Junctions and Desmosomes Coordinate Mechanics and Signaling to Orchestrate Tissue Morphogenesis and Function: An Evolutionary Perspective. Cold Spring Harb Perspect Biol 10:
Yang, Ruiguo; Broussard, Joshua A; Green, Kathleen J et al. (2018) Techniques to stimulate and interrogate cell-cell adhesion mechanics. Extreme Mech Lett 20:125-139
Broussard, Joshua A; Yang, Ruiguo; Huang, Changjin et al. (2017) The desmoplakin-intermediate filament linkage regulates cell mechanics. Mol Biol Cell 28:3156-3164
Samuelov, Liat; Li, Qiaoli; Bochner, Ron et al. (2017) SVEP1 plays a crucial role in epidermal differentiation. Exp Dermatol 26:423-430
Jones, Jonathan C R; Kam, Chen Yuan; Harmon, Robert M et al. (2017) Intermediate Filaments and the Plasma Membrane. Cold Spring Harb Perspect Biol 9:
Broussard, Joshua A; Green, Kathleen J (2017) Research Techniques Made Simple: Methodology and Applications of Förster Resonance Energy Transfer (FRET) Microscopy. J Invest Dermatol 137:e185-e191

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