A role for Delta-like homologue 1 (DLK1) in a secretory placental cell population and implications for fetal growth

Abstract

Intrauterine growth restriction (IUGR) affects between 5-10% of pregnancies carrying with it an increased risk of mortality and morbidity. Several serum analytes have been studied in the hope of finding a relevant marker linked to IUGR, but none of them have proven to be sufficiently accurate to be used in routine clinical practice as a single predictive marker. IUGR is likely to be caused by both genetic and environmental factors. Studies in rodents have identified imprinted genes as some of the major genetic modulators of intrauterine growth. In addition, misregulation of imprinted gene dosage in humans is associated with paediatric growth disorders. One such imprinted gene is Delta-like homologue 1 (DLK1). DLK1 is expressed predominantly from the paternally inherited chromosome, while the maternally inherited copy remains silent. Genetic aberrations affecting this imprinted gene cluster, as see in both humans and mouse models, result in distinct phenotypes affecting growth. A small cohort of participants was recruited from the Royal London Hospital, Fetal Medicine Unit for this study. Maternal serum DLK1 levels were measured in this preliminary cohort. DLK1 serum levels rose during gestation with levels falling after delivery. Furthermore, DLK1 was found to be predictive of birth weight and has a positive correlation with fetal growth parameters. This analysis was extended to a new cohort previously recruited at the Kuopio University Hospital, Finland. DLK1 serum levels were seen to be significantly lower in IUGR pregnancies when compared to normal pregnancies. Using immunohistochemistry methods I was able to detect robust expression of DLK1 in the fetal endothelium and trophoblast cells. Histology studies further identified the presence of multinucleated trophoblastic giant cells, a sign of maternal vascular malperfusion, as a finding in pregnancies associated with low DLK1 levels. These findings allow a better understanding of DLK1. Further investigations are warranted to enable elucidation of a mode of action for this protein.