Inactivation of the acid labile subunit gene in mice results in mild retardation of postnatal growth despite profound disruptions in the circulating insulin-like growth factor system

Insulin-like growth factors (IGFs) I and II are important regulators of cel l proliferation and differentiation. After birth, plasma IGFs, representing mostly liver-derived IGFs, circulate in ternary complexes of 150 kDa consi sting of one molecule each of ICF, IGF-binding protein (IGFBP) 3, and an ac id labile subunit (ALS). Onset of ALS synthesis after birth is the primary factor driving the formation of ternary complexes. Capture of IGFs by ALS i s thought to allow the development of a plasma reservoir without negative e ffects such as hypoglycemia and cell proliferation. To evaluate the importa nce of ALS and ternary complexes, we have created mice in which the ALS gen e has been inactivated. The mutation was inherited in a Mendelian manner, w ithout any effects on survival rates and birth weights. A growth deficit wa s observed in null mice after 3 weeks of life and reached 13% by 10 weeks. This modest phenotype was observed despite reductions of 62 and 88% in the concentrations of plasma IGF-I and IGFBP-3, respectively. Increased turnove r accounted for these reductions because indices of synthesis in liver and kidney were not decreased. Surprisingly, absence of ALS did not affect gluc ose and insulin homeostasis. Therefore, ALS is required for postnatal accum ulation of IGF-l and IGFBP-3 but, consistent with findings supporting a pre dominant role for locally produced ICF-I. is not critical for growth. This model should be useful to determine whether presence of ALS is needed for o ther actions of liver-derived ICF-I and for maintenance of homeostasis in p resence of high circulating levels of IGF-II.