The Role of the Integrin-Associated Scaffold Protein α-Parvin in Ureteric Bud Branching Morphogenesis During Kidney Development

Abstract

Branched tubular networks, including the kidney collecting system, are generated through branching morphogenesis, a developmental process that requires both new tip formation and remodeling of epithelial trunks into narrow tubules. These morphogenetic changes depend on tightly coordinated cell movement, adhesion, and rearrangement, but how integrin-associated adhesion proteins regulate these cellular behaviors remains incompletely understood. In this dissertation, we examined how α-parvin, a component of the integrin-binding ILK–PINCH–parvin complex, regulates ureteric bud branching morphogenesis and collecting duct epithelial behavior. Using three-dimensional live imaging of mouse ureteric bud development, we show that α-parvin is required for both tip branching and tubule thinning. Loss of α-parvin causes excessive cell adhesion and actin polymerization, which impairs the dynamic cell rearrangements needed to remodel the ureteric bud epithelium. Mechanistically, α-parvin promotes actin turnover by limiting activation of the small GTPases RhoA and Cdc42, thereby enhancing cofilin-mediated actin severing. These findings identify α-parvin as an important regulator of adhesion-dependent actin dynamics during epithelial branching morphogenesis. We further show that α-parvin is required for cell-cycle progression in the ureteric bud. α-Parvin promotes G1/S cell-cycle entry and is necessary for maintaining genomic stability and normal nuclear morphology. These functions may depend on α-parvin shuttling between the cytoplasm and nucleus. In support of this possibility, we identify the transcriptional repressor ZBTB2 as a potential nuclear binding partner of α-parvin, suggesting that α-parvin may regulate cell-cycle progression, at least in part, through ZBTB2-associated transcriptional control. Together, these findings show that α-parvin coordinates cytoskeletal remodeling and cell-cycle progression during ureteric bud morphogenesis, linking integrin-associated adhesion machinery to the cellular mechanisms that shape the developing kidney collecting system.