Targeted disruption of Pparγ1 promotes trophoblast endoreplication in the murine placenta

Abstract

In murine placentas, peroxisome proliferator-activated receptor (PPAR) {gamma}1, a nuclear receptor, is abundant at the late stage of pregnancy (E15-E16), but its functional roles are still elusive because PPAR{gamma}-full knockout embryos die early (E10). We generated mice disrupted in only Ppar{gamma}1, one of the two major mRNA splicing variants of PPAR{gamma}1. Ppar{gamma}1- knockout embryos developed normally until 15.5 dpc, but their growth was retarded thereafter and they did not survive. At 15.5 dpc, in the wild-type placentas, intense PPAR{gamma}-immunostaining was detected in sinusoidal trophoblast giant cells (sTGCs), a cell lineage that coordinates the maternal blood microcirculation in the labyrinth, whereas they were absent in the knockouts. Although Ppar{gamma}1-knockout placentas were normal in morphology, we observed severely dilated maternal blood sinuses in the labyrinth. The Ppar{gamma}1-knockout sTGCs had abnormally large nuclei, an enhanced endocycling phenotype, indicating insufficient differentiation. RNA-sequencing of the placentas showed increased expression of genes coding for nucleosome assembly factors. Labyrinthine gene expressions for atypical E2Fs and cyclin E, key drivers for endocycling, were increased >3-fold. These findings suggested that PPAR{gamma}1 plays a key role in endocycle termination.