Integrins are transmembrane receptors composed of α and β subunits that mediate interactions between cells and extracellular matrix. There are 18 α and 8 β subunits, which form dimers with different ligand binding properties. Integrins are classified into collagen, laminin and RGD binding receptors and regulate many cellular functions including adhesion, migration, proliferation, differentiation, and polarization. We previously showed the laminin binding integrins α3β1, α6β1 and α6β4 only play a minor role in kidney collecting system development. By contrast we now demonstrate that deleting the integrin α3 subunit in the developing kidney metanephric mesenchyme causes fatal renal abnormalities within a week of birth. When we introduced the same point mutations as those described in infants who died from renal dysgenesis into the extracellular domain of the α3 integrin subunit, the mice died with dysgenic kidneys, however the phenotypes were not as severe as the integrin α3-null mice. All three mice displayed severe kidney tubule and major glomerular abnormalities. As the mechanism whereby integrin α3β1-laminin interactions regulate organogenesis is unclear, we developed mice with a point mutation in the integrin binding site of the highly conserved γ1 laminin chain, which abrogates laminin- integrin binding to most laminins, without altering the structural integrity of the laminin trimer. When this mutation was introduced into the metanephric mesenchyme, the mice also developed dysplastic kidneys. Mechanistically we have preliminary evidence that in addition to the classic integrin functions of cell adhesion and migration, deleting Integrin α3β1 in polarized kidney epithelial cells causes severe proliferation defects with the cells unable to progress normally through the cell cycle. We have previously shown that Integrin α3β1 regulates Akt activation, a key requirement for cell proliferation. Taken together these new data suggest a critical role for laminin-binding integrins in nephron development and maturation, which contrasts with the mild phenotypes we found in the developing ureteric bud. Therefore, in this grant we will test the novel hypothesis that integrin α3β1 binding to laminin is critical for metanephric mesenchyme development and mutations that affect this interaction results in fatal renal dysgenesis in the following aims: 1) Define the role of integrin-laminin interactions in metanephric mesenchyme development. 2) Define the molecular mechanism whereby integrin α3β1-laminin interactions promote proliferation in metanephric mesenchyme development.