REGULATION OF THE INSULIN-LIKE GROWTH-FACTOR SYSTEM DURING NORMAL RAT LUNG DEVELOPMENT

Insulin-like growth factor (IGF)-I and IGF-II are small peptide growth factors that interact with a specific membrane receptor, the type 1 IGF receptor, to stimulate cellular proliferation and/or differentiation. The actions of these growth factors and their availability to their receptors are modulated by specific binding proteins, IGF binding protein (IGFBP)-1 through -6, which together with the IGFs and IGF receptors form the IGF system. We have analyzed RNA extracted from fetal (gestation day 16 [E16] through 22 [E22]) and adult (60-day-old) rat lung for expression of each component of the IGF system. IGF-I and -II RNAs are expressed throughout fetal development. IGF-I mRNA remained relatively constant in fetal and adult lung, whereas IGF-II RNA decreased in later gestation to levels below detection by Northern analyses in adult lung. Type 1 IGF receptor expression varied little through all ages studied, whereas the type 2 IGF receptor RNA displayed developmental regulation with a decline in expression with advancing age. IGFBP-1 transcripts were not detected in fetal or adult lung. IGFBP-2 RNA was expressed from E16 to E22, although its abundance decreased in late gestation and in adult lung, with the lowest levels of expression on day E22. IGFBP-3, -4, and -5 had similar profiles of RNA abundance, with fetuses at ages E21 and E22 displaying higher levels of transcript abundance as compared with those aged E17 to E20; the lowest RNA abundance was seen at E20. IGFBP-6, barely detectable in earlier fetal lung, increased transcript levels at fetal age E22 10-fold over fetal age E20 abundance and 35- to 50-fold in adult lung, suggesting a role for this binding protein in postnatal lung. This study presents a comprehensive overview of lung expression of the IGF system and demonstrates the developmental regulation of each component. These results are consistent with an important role for the IGF system during lung development and suggest that IGFBPs may be the mechanism for modulating the actions of the IGF peptides during this process.