Manipulation of Igf‐1 Expression in the Placenta and Impact on the Fetal Brain

Abstract

The placenta is an essential organ involved in mammalian development in utero. The main function of the placenta is the control of the transfer of nutrients and waste between mother and fetus, and production and delivery of hormones and growth factors. There is a lack of research that investigates the role of maternal and fetal genetics and molecular biology of the placenta’s impact on fetal neurodevelopment. Igf‐1 is a gene involved in mediating fetal development as well as growth of the brain. It is also involved in regulation of placental growth and transport. The placenta is the main source of fetal Igf‐1. Igf‐1 gene expression is altered in some individuals with autism spectrum disorder (ASD) which may reflect a role of Igf‐1 in ASD etiology. We previously found that prenatal stress, a risk factor for ASD, increased placental Igf‐1 expression and increased proliferation of striatal neural progenitors which express Igfreceptors. Developmental striatal changes are found in ASD. We therefore hypothesized that placental alterations in Igf‐1 lead to ASD‐relevant brain changes. Methods We examined this through the use of CRISPR Igf‐1 overexpression or control plasmids directly injected in mouse placenta on embryonic day 12, with subsequent tracking of changes in placenta, fetal body, and fetal brain. Igf‐1 overexpression in placenta had a variable trajectory. While placental weight was unaffected by Igf‐1 overexpression at E18, we found developmental and morphological changes of the embryo, including larger body and larger size and altered morphology of the head (macrocephaly) at E18. Brain volume measures demonstrate a range of effects on the primordial cortex and striatum at E14 and E18. One outcome of this work is advancements in methodology for understanding how placental genetics affect the development of the fetal brain. We also conclude that placental Igf‐1 expression does influence offspring growth and ASD‐relevant brain outcomes which suggests a role for placental genetics in neurodevelopmental disorders.