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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Forkhead factor FoxO1 is essential for placental morphogenesis in the developing embryo
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Forkhead factor FoxO1 is essential for placental morphogenesis in the developing embryo

机译：前叉因子FoxO1对发育中的胚胎的胎盘形态发生至关重要

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摘要

Forkhead box O1 (FoxO1), a member of the Forkhead box-containing O family of transcription factors, is a key regulator of numerous genes that govern a wide array of cellular functions, including differentiation, homeostasis, and survival. However, the role of FoxO1 in development remains elusive. Here, we describe an essential and previously undefined role for FoxO1 in placental development. We demonstrate that FoxO 7-null embryos up to embryonic day 9.0 (E9.0) are indistinguishable, including their morphology, cardiovascular structure, and vascular gene expression, from wild-type (WT) littermates. However, FoxOf-nulls manifested a profoundly swollen/hydropic allantois, which failed to fuse with the chorion, a phenotype that leads to subsequent cardiovascular malformation, progressive apoptotic cell death, and embryonic lethality at E10.5. Quantitative RT-PCR analysis of genes involved in placental development revealed significant attenuation of VCAM1 expression in FoxO1-null embryos. Using immuno-histochemical, transcriptional, and chromatin immunoprecipitation assays, we further discovered that FoxO1 is an essential upstream regulator of the VCAM1 gene. Collectively, our findings provide critical molecular insight into a unique FoxO1-VCAM1 axis that governs placental morphogenesis, a process that is essential for subsequent normal cardiovascular development and fetal life.
机译：叉头盒O1（FoxO1）是包含叉头盒的O转录因子家族的成员，是调控许多细胞功能（包括分化，体内平衡和存活）的众多基因的关键调节剂。但是，FoxO1在开发中的作用仍然难以捉摸。在这里，我们描述了FoxO1在胎盘发育中的重要作用和以前未定义的作用。我们证明，直到胚胎第9.0天（E9.0）为止，FoxO 7无效的胚胎都无法与野生型（WT）同窝仔区别开，包括它们的形态，心血管结构和血管基因表达。但是，FoxOf-nulls表现出明显的肿胀/水溶性尿囊，未能与绒毛膜融合，这种表型导致随后的心血管畸形，进行性凋亡的细胞死亡和E10.5处的胚胎致死率。胎盘发育相关基因的定量RT-PCR分析显示，FoxO1无效胚胎中VCAM1表达明显减弱。使用免疫组织化学，转录和染色质免疫沉淀测定法，我们进一步发现FoxO1是VCAM1基因的重要上游调节剂。总的来说，我们的发现为控制胎盘形态发生的独特FoxO1-VCAM1轴提供了关键的分子洞察力，这一过程对于随后的正常心血管发育和胎儿生命至关重要。

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    Anwarul Ferdous; Jesse Morris; Mohammad Joynal Abedin; Shandon Collins; James A. Richardson; Joseph A. Hill;

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    Departments of lnternal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390-8573;

    Departments of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573;

    Departments of lnternal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390-8573;

    Departments of lnternal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390-8573;

    Departments of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573,Departments of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573;

    Departments of lnternal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390-8573,Departments of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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