Human insulin-like growth factor binding protein-1 (hIGFBP-1) transgenic mice: insights into hIGFBP-1 regulation and actions.

Three hemizygous transgenic (Tg) mouse lines were generated with a fusion gene composed of the mouse metallothionein promoter (mMT-1) and a full length human insulin-like growth factor binding protein-1 (hIGFBP-1) cDNA that was truncated in its 3' untranslated (3'UT) region. The transgene was ectopically expressed in the brain of each line and resulted in postnatal brain-growth retardation that was manifested by 2 weeks of age. Despite the expression of the transgene in multiple other tissues and high serum hIGFBP-1 concentrations in two of the three lines, studies designed to detect alterations in somatic growth, in reproduction and in glucose metabolism revealed few other abnormalities. Unexpectedly, however, we found that the regulation of the transgene shared characteristics with that of the native gene, despite the fact that it lacked the endogenous gene's 5' regulatory region, as well as most of its 3' UT region. Our studies suggest that factors controlling mRNA stability are important to regulation of both the native and transgene, and that an AU-rich element 17 base pairs (bp) from the end of coding sequence is responsible for the instability of the transgene and in part for instability of the endogenous gene.