Abstract
The epidermis is a multi-layered epithelium that serves as a barrier against water loss and environmental insults. Its morphogenesis occurs through a tightly regulated program of biochemical and architectural changes during which basal cells commit to differentiate and move towards the skin's surface. Here, we reveal an unexpected role for the vertebrate cadherin desmoglein 1 (Dsg1) in remodeling the actin cytoskeleton to promote the transit of basal cells into the suprabasal layer through a process of delamination, one mechanism of epidermal stratification. Actin remodeling requires the interaction of Dsg1 with the dynein light chain, Tctex-1 and the actin scaffolding protein, cortactin. We demonstrate that Tctex-1 ensures the correct membrane compartmentalization of Dsg1-containing desmosomes, allowing cortactin/Arp2/3-dependent perijunctional actin polymerization and decreasing tension at E-cadherin junctions to promote keratinocyte delamination. Moreover, Dsg1 is sufficient to enable simple epithelial cells to exit a monolayer to form a second layer, highlighting its morphogenetic potential.
| Original language | English (US) |
|---|---|
| Article number | 1053 |
| Journal | Nature communications |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2018 |
Funding
We thank Carien Niessen and Matthias Ruebsam for helpful discussions and ideas. Gifts were provided by Pierre A. Coulombe (K17 antibody), Julie Segre (K5 and K14 antibody), Kevin Pfister (Tctex-1 antibody), and Alexander Dunn (Ecad-TSMod constructs). We are grateful to the Northwestern University Skin Disease Research Center (supported by the NIH/NIAMS; 5P30AR057216-08) for help with histological analysis of organo-typic raft cultures. Any opinions, findings, and conclusions expressed in this material are those of the author(s) and do not necessarily reflect the views of the Northwestern University Skin Disease Research Center or NIH/NIAMS. We also thank the North-western University Center for Advanced Microscopy (generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center) for assistance with imaging work. Structured illumination microscopy was performed on a Nikon N-SIM system, purchased through the support of NIH 1S10OD016342-01; FRET analysis was performed on an Andor XDI Revolution microscope, purchased through the support of NCRR S10 RR031680-01; laser ablation experiments were performed on the A1R-MP+ multiphoton microscope, purchased through an S10 shared instrumentation grant awarded to Teng-Leong Chew (1 S10 OD010398-01); time-lapse imaging of MDCK cell extrusion was performed on Nikon Biostation system, acquired through the generous support from Northwestern University Office for Research and Skin Disease Research Center. This work was supported by NIH grants R01 AR041836, R37 AR043380 with partial support from R01 CA122151, the J.L. Mayberry Endowment to K. Green and the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust. O.N. was supported by a 2014 Dermatology Foundation Research grant. J.A.B. was supported by a Training Grant, T32 AR060710.
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy