75 AKT1 deficiency is linked to placental, fetal, and postnatal growth restriction

Abstract

The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is involved in many biological processes including cell differentiation and migration. AKT1 is a serine/threonine kinase that has been implicated in fetal, placental, and postnatal growth. However, little is known about the role of AKT1 in trophoblast cell invasion and trophoblast-guided spiral artery remodeling. The objective of this project is to examine the role of AKT1 in the rat, a model of hemochorial placentation. A germline mutant Akt1 rat model using CRISPR/Cas9 genome editing was created. Mating of heterozygotes produced the expected Mendelian ratio. Western blotting was used to determine concentrations of AKT1, total AKT, and phosphorylated AKT (Ser473) proteins. Postnatal growth of AKT1 null male and female progeny was compared to wild-type progeny. Placental and fetal weights were examined. Gene expression within placentation sites was assessed. The AKT1 protein was not detected in homozygous Akt1 mutant placentas. Akt1 null male and female progeny showed significant deficits in postnatal growth. Growth restriction associated with AKT1 deficiency began in utero and was characterized by small fetuses and placentas. Postnatal growth deficiency persisted through 8 weeks of development. Interrogation of placentation sites identified growth restriction of the junctional zone and the labyrinth zone compartments of placentas from Akt1 null rats. AKT1 deficiency affected the transcriptomic phenotype of invasive trophoblast cells and trophoblast cells within the junctional zone. AKT1 is required for fetal and placental development and postnatal growth in the rat model of hemochorial placentation. AKT1 serves as a regulator of junctional zone development, the site of invasive trophoblast progenitor cells, and the invasive trophoblast cell lineage. (Supported by NIH grants HD020676, HD099638, and the Sosland Foundation).