Mystery solved: discovery of a novel integrin ligand in the developing kidney

Abstract

Mutant mice lacking the integrin alpha8 subunit exhibit variable defects in kidney development with most mutants missing both kidneys. Several lines of evidence indicate that the known extracellular matrix ligands for integrin alpha8beta1 are either dispensable for or not involved in alpha8beta1 signaling during kidney development. This suggests the presence of an unknown ligand. A novel alpha8beta1 ligand, nephronectin, has now been identified. Nephronectin is a new extracellular matrix protein associated with the Wolffian duct and the ureteric bud, epithelial structures with well-defined roles in kidney development.

Figure 1.

Schematic representation of early kidney development with known and hypothesized locations of nephronectin (yellow) and integrin α8 (red) indicated. The interaction of integrin α8-expressing mesenchymal cells with nephronectin in the ureteric bud basement membrane is critical for normal ureteric bud outgrowth and branching. (A) Embryonic day (e) 10.5. The ureteric bud (UB) has just begun to bud from the Wolffian duct (WD). Nephronectin is associated with the Wolffian duct and ureteric bud basement membranes. Integrin α8 is present on the mesenchymal cells immediately adjacent to basement membranes and elsewhere in the urogenital ridge but not in the MM. (B) e11. The ureteric bud has invaded the MM. Integrin α8 now becomes detectable on the condensing cells in the MM near the tip of the bud. (C) e11.5. The MM has induced the ureteric bud to branch. Nephronectin is found throughout the ureteric bud basement membrane, and mesenchymal cells expressing integrin α8 are found both along the proximal stalk of the ureteric bud and adjacent to the branched ureteric bud.