THE EXPRESSION OF INSULIN-LIKE GROWTH-FACTOR (IGF)-BINDING PROTEIN-2 AND IGF-II GENES IN THE TISSUES OF THE DEVELOPING OVNE FETUS

Insulin-like growth factor-II (IGF-II) regulates the growth and differentiation of tissues during fetal life and is bound to a significant extent to IGF-binding protein-2 (IGFBP-2) in blood and tissue fluids during this period of development. We have compared the expression of IGFBP-2 and IGF-II genes during development by determining the levels of stable mRNAs in various tissues of fetal [60 days gestational age to term (145-147 days)] and postnatal sheep [lambs (2 days, 4 weeks and 9 weeks) and adults; n = 3-4 in each age group). Both IGFBP-2 and IGF-II mRNAs were observed from day 50 of gestation onward. The level of IGF-II mRNAs was high in fetal tissues from early gestational ages and decreased with maturation. Seven IGF-II mRNA transcripts [1.2-6 kilobases (kb)] were expressed by most tissues except the adult liver, which expressed only a single 5.1-kb transcript, and the choroid plexus, which expressed only six transcripts. A single IGFBP-2 transcript of approximately 1.5 kb was observed. Expression of the IGFBP-2 gene was ubiquitous in tissues from fetuses younger than 80 days gestational age, but from 120 days, it was restricted mainly to the liver, kidney, and choroid plexus. In general, the IGFBP-2 mRNA level in tissues was high in early gestation and decreased with maturation, thus following the same pattern of expression as IGF-II. However, this pattern was reversed in the liver. The concurrent expression of both IGFBP-2 and IGF-II mRNAs in the same tissues in early pregnancy suggests that both proteins are synthesized together in these tissues and act by autocrine and/or paracrine mechanisms. In later gestational ages and early postnatal life, when IGF-II mRNAs were expressed in decreasing levels, IGFBP-2 mRNA was present only in selected tissues. Liver was the only tissue that continued to express abundant IGFBP-2 mRNA levels, indicating that it was the major source of this BP at later gestational ages and postnatal life, when the protein functions as an endocrine factor. Plasma IGFBP-2 levels were relatively low in fetuses of early gestational ages (<0.5 gestation) when most tissues were expressing this gene. Instead, plasma IGFBP-2 levels appeared to mirror the level of IGFBP-2 mRNA in the liver, further supporting the hypothesis that liver IGFBP-2 gene expression is the principal determinant of plasma IGFBP-2 levels. The correlation between IGFBP-2 and IGF-II mRNA levels in fetal tissues, indicates a tissue-specific coordinated regulatory role for IGF-II and IGFBP-2 during development.