Overexpression of the acid-labile subunit of the IGF ternary complex in transgenic mice

The ternary complex, composed of IGF-I or IGF-II, IGF-binding protein-3, an d the acid-labile subunit, is responsible for transport of the majority of the IGF-I and IGF-II present in the circulation. Acid-labile subunit is dev elopmentally and hormonally regulated, suggesting an important, although un clear, role in regulating the availability and action of the IGFs. To inves tigate the biological role of acid-labile subunit, we generated transgenic mice, which constitutively overexpress a hum an acid-labile subunit cDNA dr iven by the cytomegalovirus promoter. Two independent transgenic strains, C MVALS-1 and CMVALS-2, with mean serum levels of human acid-labile subunit o f 19.3 +/- 4.2 and 20.2 +/- 3.2 mug/ml respectively, were characterized. To tal acid-labile subunit, endogenous plus transgene derived, was measured by Western blotting and was found to be significantly increased in transgenic compared with wild-type mice (1.51 +/- 0.02-fold; P < 0.001). There were n o significant differences in serum IGF-binding protein-3 or IGF-I levels be tween transgenic and wildtype mice. Similar chromatographic elution pattern s were observed when sera from transgenic and wild-type mice were preincuba ted with [I-125]IGF-I, indicating that acid-labile subunit overexpression h ad no measurable effect on compartmentalization of IGF-I in the circulation . Transgene-derived human acid-labile subunit mRNA was detected in 17-d-old embryos and all adult mouse tissues examined. A significant reduction in litter size was also observed in each of the aci d-labile subunit transgenic mouse strains. This reduction in litter size wa s due to a maternal effect, as it was apparent when transgenic female mice were crossed with wild-type male mice, but not when male transgenic mice we re crossed with female wild-type mice. The transgenic mice were phenotypically normal at birth, but demonstrated a significant reduction in postnatal body weight gain, particularly during t he first 3 wk of life. Over the first 3 months of life, average body weight s were significantly reduced by 5.3 +/- 0.6%, 4.2 +/- 0.6%, 8.1 +/- 0.9%, a nd 5.6 +/- 0.8%, compared with those in wild-type mice, for male and female CMVALS-1 mice and male and female CMVALS-2 mice, respectively. Double tran sgenic mice, generated by crossing acidlabile subunit transgenic mice with transgenic mice that overexpress IGF-binding protein-3, demonstrated a sign ificantly more marked reduction in body weight gain than acid-labile subuni t transgenic mice. These data demonstrate that overexpression of acid-labile subunit has signi ficant effects on postnatal growth and reproduction. As there is little mea surable alteration in the circulating components of the IGF system, these e ffects are most likely to be mediated via disturbances in tissue IGF availa bility.