OVEREXPRESSION OF HUMAN INSULIN-LIKE GROWTH FACTOR-II IN TRANSGENIC MICE CAUSES INCREASED GROWTH OF THE THYMUS

In order to determine the effects of IGF-II overexpression on growth o f mice, transgenic mice were produced carrying one of three different H-2K(b) human IGF-II minigenes in which different non-coding exons (ex on 5, truncated exon 5 or exon 6) preceded the coding exons 7, 8 and 9 . These were spaced by truncated introns and for proper polyadenylatio n an SV40 polyadenylation signal was incorporated. The highest levels of IGF-II minigene mRNA expression were found in lines containing the truncated exon 5 construct (II5'). Those containing exon 6 (II6) had l ess expression and 5 constructs (II5) gave only moderate levels of mRN A expression. In general mRNA expression was highest in thymus and spl een, low in liver and kidney and absent in the brain. In addition, one 115' line showed expression in the brain. Serum IGF-II levels at 8 we eks of age were increased 7- to 8-fold in homezygous transgenic lines with construct 115' without brain expression and 2- to 3-fold in the o ne that showed expression in the brain; serum IGF-I levels were unchan ged. Serum IGFs in the lines containing the constructs II5 and II6 wer e not different from those of the controls. In all cases body length a nd weight as well as the weight of several organs such as brain, liver , kidneys, heart and spleen when expressed as a function of age did no t differ from controls. Only the thymus showed a significant increase in weight in the transgenics II5'. Inbreeding of 2 lines containing co nstruct II5' with pituitary deficient Snell dwarf mice did not influen ce body length or weight despite increased serum IGF-II levels. Again the thymus showed a marked increase in growth. The biological activity of the IGF-II peptide was further demonstrated by increased serum IGF -binding protein-3 in the transgenic dwarf mice, as shown by Western L igand blotting. In summary, overexpression of IGF-II in transgenic nor mal and dwarf mice does not affect overall body growth, but causes inc reased growth of the thymus. This suggests a role for IGF-II in thymic development by paracrine/autocrine action.