Actin Depolymerizing Factors Cofilin1 and Destrin Are Required for Ureteric Bud Branching Morphogenesis

Satu Kuure,Deborah Hyink,Cristina Cebrian,Benson C Lu,Walter Witke,Christine Gurniak,Quentin Machingo,Vivette D'Agati,Frank Costantini,Xuan Chi

doi:10.1371/journal.pgen.1001176

Abstract

The actin depolymerizing factors (ADFs) play important roles in several cellular processes that require cytoskeletal rearrangements, such as cell migration, but little is known about the in vivo functions of ADFs in developmental events like branching morphogenesis. While the molecular control of ureteric bud (UB) branching during kidney development has been extensively studied, the detailed cellular events underlying this process remain poorly understood. To gain insight into the role of actin cytoskeletal dynamics during renal branching morphogenesis, we studied the functional requirements for the closely related ADFs cofilin1 (Cfl1) and destrin (Dstn) during mouse development. Either deletion of Cfl1 in UB epithelium or an inactivating mutation in Dstn has no effect on renal morphogenesis, but simultaneous lack of both genes arrests branching morphogenesis at an early stage, revealing considerable functional overlap between cofilin1 and destrin. Lack of Cfl1 and Dstn in the UB causes accumulation of filamentous actin, disruption of normal epithelial organization, and defects in cell migration. Animals with less severe combinations of mutant Cfl1 and Dstn alleles, which retain one wild-type Cfl1 or Dstn allele, display abnormalities including ureter duplication, renal hypoplasia, and abnormal kidney shape. The results indicate that ADF activity, provided by either cofilin1 or destrin, is essential in UB epithelial cells for normal growth and branching.

Highlights

Depolymerization and severing of actin filaments produces new actin monomers and new free ends that facilitate dynamic changes in the actin cytoskeleton
In order to investigate the requirement for actin depolymerization factors (ADFs) activity in ureteric bud morphogenesis, we studied the effects Dstn and Cfl1 mutations during renal development, initially using conventional
While the UB epithelium was clearly devoid of cofilin1 at E11.5 and E12.5 (Figure 3C–3D’), confirming the activity of Hoxb7/ CreGFP, we found that cofilin1 protein levels at E10.5 were normal in the forming ureteric bud (Figure 3A–3B’)

Summary

Introduction

Depolymerization and severing of actin filaments produces new actin monomers and new free ends that facilitate dynamic changes in the actin cytoskeleton. These events are essential for several cellular processes including cell survival, shaping, cytokinesis, migration and chemotaxis [1]. ADF genes share overlapping expression patterns in many cell types, but the phenotypes of mouse mutants in either Cfl or Dstn suggest that they have somewhat distinct in vivo functions. While Dstn2/2 brains have a normal gross morphology, conditional deletion of Cfl in neuronal cells causes excessive differentiation, changes in cell proliferation, and migration defects, resulting in a lissencephaly phenotype [5]

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Results

Conclusion