Effects of Pparγ1 deletion on late-stage murine embryogenesis and cells that undergo endocycle
Effects of Pparγ1 deletion on late-stage murine embryogenesis and cells that undergo endocycle
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Pparγ1缺失对晚期小鼠胚胎发生和内周期细胞的影响
DOI：
10.1016/j.ydbio.2021.07.003
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发表时间：
2021
影响因子：
2.7
通讯作者：
Inoue Ikuo
中科院分区：
文献类型：
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作者：
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
过氧化物酶体增殖物激活受体（Peroxisome proliferator-activated receptor，PPAR）γ1是一种核受体，在妊娠晚期（E15-E16）小鼠胎盘中大量表达，但其功能尚不清楚。PPARγ1由两种剪接异构体Ppar γ 1canonical和Ppar γ 1 sv编码，其胚胎丢失导致早期（E10）胚胎死亡。因此，我们制备了只携带一种亚型的敲除（KO）小鼠，以获得更温和的表型。Pparγ 1 sv-KO小鼠能够存活并具有生育能力，而Ppar γ1canonical-KO小鼠在断奶时无法恢复。Pparγ1canonical-KO胚胎在15.5 dpc时发育正常，之后生长延迟。Ppar γ 1标准-KO胎盘结合区严重浸润迷路，母体血窦扩张。在野生型中，PPARγ1在窦状隙滋养层巨细胞（S-TGCs）中高度表达，在15.5 dpc时达到峰值，Pparγ1canonical-KO可阻断S-TGCs中的PPARγ1表达。值得注意的是，S-TGCs具有异常增大的核，并且经常占据母体血管空间，扰乱了精细迷路结构的组织。Ppar γ 1标准基因敲除胎盘的基因表达分析显示S期细胞周期特征增强。Ppar γ 1标准-KO胎盘中EdU阳性S-TGCs的数量多于野生型胎盘，表明突变胎盘中细胞继续进行内复制。这些结果表明，PPARγ1，一个已知的细胞周期阻滞介质，参与了转变的TGCs进行内循环到终末分化阶段的胎盘。因此，通过遗传操作诱导的PPARγ1缺乏导致胎盘功能不全。
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, namelyPparγ1canonicalandPparγ1sv,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, whereasPparγ1canonical-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 ofPparγ1canonical-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 ofPparγ1canonical-KO placentas indicated enhanced S-phase cell cycle signatures. EdU-positive S-TGCs inPparγ1canonical-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.