KLF5 Shapes Developing Respiratory Tubules by Inhibiting Actin Asymmetry in Epithelial Cells

Tubulogenesis depends on precise cell shape changes driven by asymmetric tension from the actin cytoskeleton. How actin asymmetry is dynamically controlled to coordinate epithelial cell shape changes required for respiratory tubulogenesis remains unknown. Herein, we unveiled a critical role for the transcription factor KLF5, regulating actin asymmetry, inducing epithelial cell shape changes by balancing RHOA and CDC42 GTPase activity via RICH2. Conditional Klf5 expression or deletion in pulmonary epithelial cells affected apical actin organization and the positioning of apical polarity proteins in cell membranes, disrupting branching and sacculation of respiratory tubules during mouse lung morphogenesis. Increased KLF5 concentrations were observed in epithelial cells lining dilated tubules in lungs from patients with congenital pulmonary airway malformation. Together, our results demonstrate that dynamic regulation of apical actin organization by KLF5 is essential for respiratory tubulogenesis, providing a mechanistic framework for comprehending the morphogenesis of respiratory tubules.