TY - JOUR
T1 - Desmosomes polarize and integrate chemical and mechanical signaling to govern epidermal tissue form and function
AU - Broussard, Joshua A.
AU - Koetsier, Jennifer L.
AU - Hegazy, Marihan
AU - Green, Kathleen J.
N1 - Funding Information:
We thank Alpha Yap, Andrew Kowalczyk, Lisa Godsel, and Quinn Roth-Carter for helpful feedback on the manuscript. Research reported in this publication was supported by Northwestern University Skin Biology & Diseases Resource-Based Center of the National Institutes of Health under award number P30AR075049. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Multiphoton microscopy was performed on a Nikon A1R multiphoton microscope, acquired through the support of NIH 1S10OD010398-01. This work was supported by NIH grants R01 AR041836 and R37 AR043380, with partial support from R01 CA228196, the J.L. Mayberry Endowment to K.J.G. and the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust. M.H. was supported by NIH F31 AR076188. J.A.B. was supported by NIH K01 AR075087 and T32 AR060710. Conceptualization, J.A.B. and K.J.G.; methodology, J.A.B. and J.L.K.; investigation, J.A.B. J.L.K. and M.H.; writing – original draft, J.A.B. and K.J.G.; writing – review & editing, J.A.B. J.L.K. M.H. and K.J.G.; visualization, J.A.B. J.L.K. and M.H.; supervision, K.J.G.; funding acquisition, J.A.B. and K.J.G. The authors declare no competing interests.
Funding Information:
We thank Alpha Yap, Andrew Kowalczyk, Lisa Godsel, and Quinn Roth-Carter for helpful feedback on the manuscript. Research reported in this publication was supported by Northwestern University Skin Biology & Diseases Resource-Based Center of the National Institutes of Health under award number P30AR075049 . Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center . Multiphoton microscopy was performed on a Nikon A1R multiphoton microscope, acquired through the support of NIH 1S10OD010398-01 . This work was supported by NIH grants R01 AR041836 and R37 AR043380 , with partial support from R01 CA228196 , the J.L. Mayberry Endowment to K.J.G. and the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust . M.H. was supported by NIH F31 AR076188 . J.A.B. was supported by NIH K01 AR075087 and T32 AR060710 .
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/8/9
Y1 - 2021/8/9
N2 - The epidermis is a stratified epithelium in which structural and functional features are polarized across multiple cell layers. This type of polarity is essential for establishing the epidermal barrier, but how it is created and sustained is poorly understood. Previous work identified a role for the classic cadherin/filamentous-actin network in establishment of epidermal polarity. However, little is known about potential roles of the most prominent epidermal intercellular junction, the desmosome, in establishing epidermal polarity, in spite of the fact that desmosome constituents are patterned across the apical to basal cell layers. Here, we show that desmosomes and their associated intermediate filaments (IFs) are key regulators of mechanical polarization in epidermis, whereby basal and suprabasal cells experience different forces that drive layer-specific functions. Uncoupling desmosomes and IF or specific targeting of apical desmosomes through depletion of the superficial desmosomal cadherin, desmoglein 1, impedes basal stratification in an in vitro competition assay and suprabasal tight junction barrier functions in 3D reconstructed epidermis. Surprisingly, disengaging desmosomes from IF also accelerated the expression of differentiation markers, through precocious activation of the mechanosensitive transcriptional regulator serum response factor (SRF) and downstream activation of epidermal growth factor receptor family member ErbB2 by Src family kinase (SFK)-mediated phosphorylation. This Dsg1-SFK-ErbB2 axis also helps maintain tight junctions and barrier function later in differentiation. Together, these data demonstrate that the desmosome-IF network is a critical contributor to the cytoskeletal-adhesive machinery that supports the polarized function of the epidermis.
AB - The epidermis is a stratified epithelium in which structural and functional features are polarized across multiple cell layers. This type of polarity is essential for establishing the epidermal barrier, but how it is created and sustained is poorly understood. Previous work identified a role for the classic cadherin/filamentous-actin network in establishment of epidermal polarity. However, little is known about potential roles of the most prominent epidermal intercellular junction, the desmosome, in establishing epidermal polarity, in spite of the fact that desmosome constituents are patterned across the apical to basal cell layers. Here, we show that desmosomes and their associated intermediate filaments (IFs) are key regulators of mechanical polarization in epidermis, whereby basal and suprabasal cells experience different forces that drive layer-specific functions. Uncoupling desmosomes and IF or specific targeting of apical desmosomes through depletion of the superficial desmosomal cadherin, desmoglein 1, impedes basal stratification in an in vitro competition assay and suprabasal tight junction barrier functions in 3D reconstructed epidermis. Surprisingly, disengaging desmosomes from IF also accelerated the expression of differentiation markers, through precocious activation of the mechanosensitive transcriptional regulator serum response factor (SRF) and downstream activation of epidermal growth factor receptor family member ErbB2 by Src family kinase (SFK)-mediated phosphorylation. This Dsg1-SFK-ErbB2 axis also helps maintain tight junctions and barrier function later in differentiation. Together, these data demonstrate that the desmosome-IF network is a critical contributor to the cytoskeletal-adhesive machinery that supports the polarized function of the epidermis.
KW - ErbB receptors
KW - cell and tissue mechanics
KW - cytoskeleton
KW - desmoglein
KW - desmoplakin
KW - epidermal morphogenesis
KW - epithelial polarity
KW - intermediate filaments
KW - tight junctions
UR - http://www.scopus.com/inward/record.url?scp=85111861349&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85111861349&partnerID=8YFLogxK
U2 - 10.1016/j.cub.2021.05.021
DO - 10.1016/j.cub.2021.05.021
M3 - Article
C2 - 34107301
AN - SCOPUS:85111861349
VL - 31
SP - 3275-3291.e5
JO - Current Biology
JF - Current Biology
SN - 0960-9822
IS - 15
ER -