Targeted gene mutations define the roles of insulin and IGF-I receptors inmouse embryonic development

Insulin-like growth factors (IGFs) and their receptors regulate embryonic a nd post-natal growth. Genetic evidence derived from targeted mouse mutants indicates that both the insulin receptor (IR) and IGF-I receptors (IGF-IRs) are required for mouse embryonic growth. However, the roles of IRs and IGF -IRs are functionally distinct, with IGF-IRs mediating both IGF-I and IGF-I I actions, and IRs mediating IGF-II, rather than insulin, action. The combi ned interactions of IGF-IRs and IRs with IGF-I and IGF-II account for the e ntirety of the growth effects of these two ligands, and provide the molecul ar basis for IGFs-mediated intrauterine growth and differentiation. Genetic ablation experiments of insulin receptor substrate-1 (IRS-1) and -2 (IRS-2 ), two important molecules in the IR and IGF-IR signaling pathways, are als o beginning to shed light onto the mechanisms accounting for the specificit y of IR and IGF-IR signaling, IRS-1-deficient mice are growth retarded, whi le IRS-2-deficient mice develop diabetes, indicating that the two molecules play a more specific role than previously recognized in IGF-IR and IR sign aling.