DEVELOPMENTAL EXPRESSION OF INSULIN-LIKE GROWTH-FACTOR-II RECEPTOR (IGF-IIR) IN CONGENIC MOUSE EMBRYONIC LUNGS - CORRELATION BETWEEN IGF-IIR MESSENGER-RNA AND PROTEIN-LEVELS AND HETEROCHRONIC LUNG DEVELOPMENT

Embryonic lung maturation ill the H-2 congenic pair, B10.A and B10, pr oceeds at different rates. The dependence of this heterochronic develo pment on maternal haplotype suggests the involvement of a parentally i mprinted gene, Since B10.A(H-2(a)) and B10 (H-2(b)) mice are genetical ly identical except for a 3-18 cM region of chromosome 17 that include s the H-2 complex, we sought a promising candidate gene(s) involved in regulating the rate of lung development from genes encoded in this re gion. The best candidate is the gene encoding the type II insulin-like growth factor receptor (IGF-IIR), whose ligand is the growth factor I GF-II. Only the maternal copy of this gene is expressed in postimplant ation embryos. This receptor does not appear to transduce mitogenic si gnals; instead, IGF-IIR appears to regulate the levels of its ligand a vailable to the growth-promoting type I IGF receptor (IGF IR). Using i n situ hybridization and indirect immunofluorescence, we demonstrate t hat IGF-IIR mRNA and protein are localized throughout the pulmonary me senchyme, as well as in branching epithelia of the pseudoglandular and canalicular stages. We also examined the levels of IGF-IIR mRNA and p rotein expression by RNase protection assay and ligand blotting during the embryonic period of lung development in B10.A and B10 mice, and f ound that there is a highly significant positive correlation of IGF-II R levels with progressive development in both strains. Further, slower -developing B10.A lungs contain significantly higher levels of IGF-IIR mRNA and protein than the more rapidly developing B10 lungs. These re sults suggest that haplotype-dependent elevation of IGF-IIR levels red uces the available concentration of IGF-II, resulting in a decreased r ate of morphogenesis in B10.A mice, Heterochronic lung maturation, the n, appears consequent to variable extracellular levels of this importa nt growth factor. These results may be of clinical importance to predi cting susceptibility to Respiratory Distress Syndrome in prenatal newb orns. (C) 1996 Wiley-Liss, Inc.