239 Desmosomes pattern cell mechanics to govern epidermal tissue form and function

Abstract

The epidermis exhibits polarization of structural and functional features across multiple cell layers, but how this polarity is created and preserved is poorly understood. Desmosomes (DSMs) are cell-cell adhesive organelles linking to intermediate filaments (IF) and are critical for signaling and tissue integrity. The DSM cadherin desmoglein 1 (Dsg1) is first expressed as cells commit to differentiate and stratify, with expression peaking in the granular layer (SG). We hypothesize the pattern of Dsg1 and associated IF is crucial for establishing proper epidermal polarity, especially mechanical polarity. To test this, we used laser ablation and whole mount imaging to assess layer-specific mechanical properties of 3D epidermal cultures. These data support an epidermal mechanical gradient: keratinocytes are under compressive forces in the basal layer and high tension in the suprabasal layers. We previously showed Dsg1 regulates basal cell forces to promote stratification. Here, a DSM/IF uncoupling mutant recapitulates Dsg1 loss, suggesting a requirement of IF attachment. High apical tension in simple epithelia helps generate barrier-critical tight junctions (TJs). TJs localize to the SG in epidermis, where tension is high and Dsg1 expression peaks. Thus, we assessed the ability of Dsg1 to polarize tension and TJs in the SG. Dsg1 loss disrupts the polarized SG distribution of the tension sensitive TJ component ZO1. Our data suggest Dsg1 modulates TJs through the mechanosensitive kinase ErbB2, which localizes to the TJ forming layer. Dsg1 loss disrupts this localization and decreases total and phosphorylated ErbB2. Uncoupling the DSM/IF linkage or inhibiting ErbB2 significantly decreases epidermal electrical barrier function. As mechanical forces regulate cell behavior, our data suggest a model in which patterning of DSM components regulates epidermal polarity by orchestrating the distribution of mechanical inputs to drive morphogenesis and development of a life-essential barrier.