Kidney Week

Abstract: TH-PO385

α-Parvin, an Integrin-Related Scaffold Protein, Regulates Actin Dynamics to Facilitate Kidney Ureteric Bud Branching Morphogenesis

Session Information

• Development, Organoids, Injury, and Regeneration
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Development, Stem Cells, and Regenerative Medicine

• 600 Development, Stem Cells, and Regenerative Medicine

Authors

• Dong, Xinyu, Vanderbilt University, Nashville, Tennessee, United States

Xinyu Dong

• Bock, Fabian, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Fabian Bock, MD, PhD

• Pozzi, Ambra, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Ambra Pozzi, PhD, DrPH

• Zent, Roy, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Roy Zent, MD, PhD

Background

The kidney collecting system is developed from the ureteric bud (UB), which undergoes branching and tubule elongation via cell division and movement. Multiple factors, including growth factor-dependent signaling, cell-extracellular matrix (ECM) interactions, and actin dynamics are required. While extensive information exists on how growth factors regulate branching morphogenesis, significantly less is known about the roles of cell-ECM receptors and actin dynamics. Integrins, the major cell-ECM receptors, are crucial for mediating cell adhesion and signaling. Integrin function is partly mediated by the recruitment of scaffold proteins like α-parvin. Our previous research demonstrated that a global knockout of α-parvin results in kidney agenesis. However, the specific role of α-parvin in ureteric bud branching morphogenesis remains unexplored.

Methods

We deleted α-Parvin at the initiation of UB development (E10.5) by crossing the α-Parvin^fl/fl with HOXB7^Cre mice. To allow ex vivo imaging and cell tracking, we utilized membrane-tethered (mTmG) GFP mice. To study the molecular function of α-Parvin, we isolated CD cells from 8-week-old α-parvin mice and deleted the gene in vitro using adenovirus-mediated delivery of a Cre recombinase.

Results

In this study, we show that a-parvin, an integrin-associating and actin-binding protein, plays a critical role in UB development by regulating ureteric bud cell movement. We observed that the α-parvin^fl/fl:HoxB7^Cre mice exhibited severely dysmorphic kidneys and died within 2-3 months. Mutant kidneys in different embryonic stages showed a significant decrease in size and branching tips, along with widened tubules. Direct ex vivo imaging and cell tracking using the mTmG mice demonstrated that a-parvin regulates neighbor exchanges (cell intercalation) and motion persistence, which are essential for tubule narrowing. Isolated α-parvin-null CD cells had increased cell adhesion and spreading but impaired migration. Surprisingly, a-parvin mediated these effects only by regulating Rho family GTPase-dependent depolymerization of F-actin via cofilin and not by affecting integrin function.

Conclusion

We conclude that the integrin scaffold protein, α-parvin, regulates branching morphogenesis and tubule elongation of the UB by controlling actin dynamics.

Funding

• NIDDK Support