The Rho GTPase regulator ARHGEF3 orchestrates hair placode budding by coordinating cell fate and P-cadherin patterning in mice

Abstract

During embryogenesis, cells self-organize into precise patterns that enable tissues and organs to acquire specialized functions. Despite its importance, the molecular choreography driving these collective cellular behaviors remains poorly understood, posing a major challenge in developmental biology and limiting progress in regenerative medicine. Here, we use the developing mouse hair follicle as a model miniorgan to investigate the early events of epithelial bud formation. We identify the Rho GTPase regulator ARHGEF3 as a critical upstream factor that restricts cell fate acquisition and establishes a radial gradient of P-cadherin across the placode during early hair follicle development. In Arhgef3 knockout embryos, placodes are enlarged and exhibit elevated P-cadherin levels at cell-cell junctions, disrupting gradient formation without affecting E-cadherin distribution. This defect correlates with aberrant epithelial organization and increased incidence of straight hair follicle downgrowth. Our findings position ARHGEF3 as a novel regulator of cadherin patterning and placode polarization, and suggest broader roles in the morphogenesis of other epithelial appendages governed by similar developmental programs.