Abstract
Robo2 is the cell surface receptor for the repulsive guidance cue Slit and is involved in axon guidance and neuronal migration. Nephrin is a podocyte slit-diaphragm protein that functions in the kidney glomerular filtration barrier. Here, we report that Robo2 is expressed at the basal surface of mouse podocytes and colocalizes with nephrin. Biochemical studies indicate that Robo2 forms a complex with nephrin in the kidney through adaptor protein Nck. In contrast to the role of nephrin that promotes actinpolymerization, Slit2-Robo2 signaling inhibits nephrin-induced actin polymerization. In addition, the amount of F-actin associated with nephrin is increased in Robo2 knockout mice that develop an altered podocyte foot process structure. Genetic interaction study further reveals that loss of Robo2 alleviates the abnormal podocyte structural phenotype in nephrin null mice. These results suggest that Robo2 signaling acts as a negative regulator on nephrin to influence podocyte foot process architecture.
Highlights
In the normal kidney, the trilaminar glomerular capillary wall, composed of fenestrated endothelial cells, basement membrane, and podocytes, restricts the permeability to plasma proteins
We report that Robo2 is expressed at the basal surface of mouse podocytes and colocalizes with nephrin
The amount of F-actin associated with nephrin is increased in Robo2 knockout mice that develop an altered podocyte foot process structure
Summary
The trilaminar glomerular capillary wall, composed of fenestrated endothelial cells, basement membrane, and podocytes, restricts the permeability to plasma proteins. Whereas genetic mutations of podocyte slit-diaphragm proteins such as nephrin and others are associated with hereditary forms of proteinuric kidney disease (Tryggvason et al, 2006), it has become evident that the proteins that make up and associate with the slit diaphragm are more than a simple structural barrier These proteins form a balanced signaling network that may influence podocyte foot process structure and function through interaction with the F-actin cytoskeleton (Faul et al, 2007; Jones et al, 2006; Verma et al, 2006). The transmembrane protein Robo contains five Ig motifs and three fibronectin type III (FNIII) repeats in its extracellular domain (Dickson and Gilestro, 2006). The repulsive Slit2-Robo signaling inhibits actin polymerization (Guan and Rao, 2003) or induces F-actin depolymerization (Piper et al, 2006)
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