Effects of Pparγ1 deletion on late-stage murine embryogenesis and cells that undergo endocycle

• Published in: Developmental biology Vol. 478; pp. 222 - 235
• Main Authors: Nakano, Takanari, Aochi, Hidekazu, Hirasaki, Masataka, Takenaka, Yasuhiro, Fujita, Koji, Tamura, Masaru, Soma, Hiroaki, Kamezawa, Hajime, Koizumi, Takahiro, Shibuya, Hirotoshi, Inomata, Reiko, Okuda, Akihiko, Murakoshi, Takayuki, Shimada, Akira, Inoue, Ikuo
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.10.2021
• Subjects: Cell cycle; Embryogenesis; Fetomaternal interface; Intrauterine growth restriction; Polyploidy; Trophoblast giant cells; Trophoblast giant cells; Intrauterine growth restriction; Embryogenesis; Polyploidy; Fetomaternal interface; Cell cycle
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2021.07.003

Peroxisome proliferator-activated receptor (PPAR) γ1, a nuclear receptor, is abundant in the murine placenta during the late stage of pregnancy (E15–E16), although its functional roles remain unclear. PPARγ1 is encoded by two splicing isoforms, namely Pparγ1canonical and Pparγ1sv, and its embryonic loss leads to early (E10) embryonic lethality. Thus, we generated knockout (KO) mice that carried only one of the isoforms to obtain a milder phenotype. Pparγ1sv-KO mice were viable and fertile, whereas Pparγ1canonical-KO mice failed to recover around the weaning age. Pparγ1canonical-KO embryos developed normally up to 15.5 dpc, followed by growth delays after that. The junctional zone of Pparγ1canonical-KO placentas severely infiltrated the labyrinth, and maternal blood sinuses were dilated. In the wild-type, PPARγ1 was highly expressed in sinusoidal trophoblast giant cells (S-TGCs), peaking at 15.5 dpc. Pparγ1canonical-KO abolished PPARγ1 expression in S-TGCs. Notably, the S-TGCs had unusually enlarged nuclei and often occupied maternal vascular spaces, disturbing the organization of the fine labyrinth structure. Gene expression analyses of Pparγ1canonical-KO placentas indicated enhanced S-phase cell cycle signatures. EdU-positive S-TGCs in Pparγ1canonical-KO placentas were greater in number than those in wild-type placentas, suggesting that the cells continued to endoreplicate in the mutant placentas. These results indicate that PPARγ1, a known cell cycle arrest mediator, is involved in the transition of TGCs undergoing endocycling to the terminal differentiation stage in the placentas. Therefore, PPARγ1 deficiency, induced through genetic manipulation, leads to placental insufficiency. [Display omitted] •PPARγ1 is highly expressed in the late-stage placenta, but its role is unknown yet.•Pparγ1−/− conceptuses produced mature placentas with impaired vascularization.•This was due to the loss of PPARγ1 in sinusoidal trophoblast giant cells (TGCs).•The nuclei of the Pparγ1−/− TGCs were huge with excess endocycling.•PPARγ1 may coordinate to exit endocycling and allow the terminal differentiation.