Maternal-fetal conflict--lessons from a transgene.

Fetal growth is a complex process that depends on the genetic makeup of the fetus, the success of the implantation process, the availability of nutrients and oxygen to the fetus, intrauterine insults (e.g., hypoxia, cigarette smoking, infection), maternal nutrition, and a variety of growth factors, cytokines, and proteins of maternal and fetal/placental origin (see refs. 1, 2 for reviews). In the maternal circulation and decidua and in the fetus, IGFs and their binding proteins (IGFBPs) and receptors are important regulators of fetal growth. The question of whether the mother or the fetus ultimately controls fetal growth and placentation has been complicated by the finding that IGFBP-1 is produced by both maternal and fetal tissues. In this issue of the JCI, Crossey et al. (3) investigate this maternal-fetal conflict by targeting over-expression of human IGFBP-1 to the mouse decidua and/or the fetus. While providing new insights as to who is in control during fetal development, these authors raise new questions about mechanisms governing fetal and placental growth and placentation. Homologous recombination studies in mice have demonstrated the importance of IGF-I and IGF-II in fetal and placental growth, respectively. Igf-1–/– pups exhibit a 40% reduction in birth weight (4). Mice lacking the type II IGF receptor, which contributes to IGF-II turnover but is not essential for transducing signals from IGF-II, exhibit a 25% increase in placental mass (5), whereas animals null for the type I (signaling) IGF receptor demonstrate severe fetal growth restriction (3). In humans, a natural deletion of exons 4 and 5 of the IGF-1 gene results in severe preand post-natal growth restriction and mental retardation (6). Furthermore, IGF-I concentrations in full-term human cord blood correlate with fetal birthweight (7–11). Together, these data underscore the importance of IGF-I in human fetal growth and development. Regulation of IGF bioavailability is tightly controlled by IGF binding proteins, a family of high-affinity proteins in the circulation, synthesized locally in tissues that are mostly inhibitory to IGF actions and that have IGFindependent actions. The literature supports a major role for elevated IGFBP-1 in the fetus in inhibiting fetal growth (12, 13), probably by sequestering fetus-derived IGF-I. IGFBP-1 concentrations in fetal blood collected by cordocentesis in the third trimester are significantly higher in growthrestricted babies than in normalweight babies (9, 10, 13). In contrast to the positive correlation between fetal serum IGF-I and birthweight, IGFBP-1 concentrations are inversely correlated with birthweight (9, 10, 13). On the maternal side, IGFBP-1 is a major product of the maternal decidua and is believed to inhibit (14) or enhance (15) trophoblast invasion into the maternal decidua, which can affect normal placental development and thus fetal growth. Commentary