Spectrin coordinates cell shape and signaling essential for epidermal differentiation

Cell shape and fate are tightly linked, yet how the cortical cytoskeletal integrates regulation of shape and fate remains unclear. Using the epidermis as a paradigm where cell shape changes guide differentiation we identify spectrin as an essential organizer of the keratinocyte actomyosin cortex that integrates transitions in cell shape with spatial organization of signaling. Loss of II-spectrin (Sptan1) in the mouse epidermis altered cell shape in all layers and impaired differentiation, and barrier formation. High-resolution imaging and laser ablation revealed that E-cadherin guides differential gradients of actin and spectrin to regulate the layer-specific organization and mechanics of sub-membraneous spectrin-actomyosin networks. This organization is essential to dissipate tension, maintain structural integrity, and retain active growth factor receptor EGFR and the cation channel TRPV3 at the membrane in upper layers to induce terminal differentiation. Together, these findings reveal how organization of the cortical cytoskeleton coordinates changes in cell shape and cell fate at the tissue scale necessary to establish epithelial barriers.