CAP1 enhances actin dynamics to control epidermal morphogenesis

Summary: Abstract Body: Epidermal development relies on precise coordination between the actin cytoskeleton and its associated adhesion structures and polarity complexes. CAP1 (cyclase-associated actin cytoskeleton regulatory protein 1), a multidomain protein known for its roles in actin remodeling and cAMP regulation, is frequently dysregulated in epithelial cancers; however, its role in epithelial development is poorly understood. Here, we identify CAP1 as a critical regulator of epidermal morphogenesis. While CAP1 loss of function did not affect cAMP levels, it significantly increased F-actin content and disrupted actin organization. In-utero depletion of Cap1 in mouse embryos revealed severe epidermal defects, including disorganized adherens junctions (AJs), disrupted apicobasal polarity, and abnormal cell shape. Despite CAP1's profound influence on the structural and molecular organization of junctional actin, CAP1 itself was not enriched at cell junctions. Live imaging demonstrated that CAP1 is essential for maintaining actin dynamics, and pharmacological stabilization of actin filaments confirmed that impaired actin dynamics are incompatible with proper AJ assembly. Moreover, mutational analysis revealed that CAP1's distinct functions in F-actin depolymerization and G-actin nucleotide exchange and CAP1's ability to interact with the actin-severing protein cofilin are essential for AJ integrity and cell shape. These findings position CAP1 as a key modulator of F-actin content, actin dynamics, and junctional organization in vitro and in vivo, offering novel insights into the cytoskeletal regulation crucial for skin development. Joby Issac¹, Chen Luxenburg¹ 1. Tel Aviv University Faculty of Medicine, Tel Aviv-Yafo, Tel Aviv District, Israel. Epidermal Structure and Barrier Function