FGD1 restrains actomyosin contractility to promote suprabasal junction maturation in stratified keratinocytes.

Abstract

The epidermis is a stratified epithelium in which keratinocytes differentiate as they move from basal to suprabasal layers, a process during which tissue integrity relies on the coordinated remodeling of intercellular junctions and the cytoskeleton. Unlike simple epithelia, which form a continuous zonula adherens, suprabasal cells in the epidermis lack a canonical junction belt, with E-cadherin-based junctions distributed across the entire cell surface, highlighting distinct regulatory mechanisms that remain poorly understood. Here, we identify the CDC42 guanine nucleotide exchange factor FGD1, mutated in Aarskog-Scott syndrome, as a regulator of suprabasal junction architecture. Using stratified human keratinocytes and quantitative imaging, we show that loss of FGD1 induces elongated radial actin bundles and tortuous, tension-associated adherens junctions resembling the stress fiber-anchored discontinuous (focal) adherens junctions described in endothelial cells. These defects are accompanied by altered tissue mechanics. Inhibition of ROCK or myosin II restores junction organization, demonstrating that FGD1 restrains actomyosin contractility to promote suprabasal junction maturation. Several disease-associated FGD1 variants fail to rescue these defects. Together, our findings identify FGD1 as a regulator of suprabasal junction maturation.