Mechanisms of trophoblast lineage formation: Impact on postimplantation placental development

滋养层谱系形成机制：对植入后胎盘发育的影响

基本信息

批准号：
9898405
负责人：
Jason Glenn Knott
金额：
$ 32.16万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9898405
关键词：
Abnormal placentation Address Biogenesis Bioinformatics Biological Assay Biological Models CDX2 gene Cell Lineage Cell Polarity Cell division Cell model Cells Chorion Clinical Co-Immunoprecipitations Complex Conceptus Cone Data Development Disease Ectoderm Embryo Embryo Loss Etiology Event Failure Fertility Fetal Growth Frequencies Gene Expression Gene Expression Profiling Genetic Transcription Goals Growth Health Hormones Human Infertility Inner Cell Mass Knowledge Lead Life Cycle Stages Mediating Microscopy Molecular Mus National Institute of Child Health and Human Development Oocytes Placenta Placenta Diseases Placentation Positioning Attribute Pre-implantation Embryo Development Pregnancy Process Production Regulation Reproduction Research Priority Role Signal Transduction Signaling Protein Spontaneous abortion Syncytiotrophoblast Testing Tight Junctions Time Transcription Factor AP-2 Gamma Transcriptional Regulation Work blastocyst cell type dosage early pregnancy loss embryonic stem cell experimental study failure Implantation gain of function human embryonic stem cell insight loss of function novel placental mammal polarized cell preimplantation progenitor programs reproductive stem cell model stem cells transcription factor trophoblast

项目摘要

SUMMARY Trophoblast lineage formation represents the first differentiation event in the life cycle of placental mammals. This process begins in the preimplantation embryo and continues in the postimplantation conceptus. Failure to accurately establish the trophoblast lineage has major consequences, including developmental arrest prior to the blastocyst stage, implantation failure, early miscarriage, and placental abnormalities. The overall objective of the proposed studies is to use mouse embryos, and mouse and human embryonic stem (ES) cells as model systems to elucidate the transcriptional mechanisms that govern trophoblast lineage development. Preliminary studies discovered a novel and critical role for transcription factor AP-2γ (TFAP2C) in triggering and regulating key events that underlie trophoblast lineage development. The overall hypothesis is that TFAP2C is a key orchestrator of trophoblast lineage formation in mice and humans, whose precise regulation during the window of preimplantation development is critical for postimplantation placental development. Studies in Specific Aim 1 will determine the role of TFAP2C in mouse trophoblast lineage formation. Experiments will test the hypothesis that TFAP2C induces a trophoblast cell-fate in preimplantation embryos by positively regulating the formation of polar-outside cells. Work in Specific Aim 2 will define the molecular mechanism by which TFAP2C induces a trophoblast gene expression program in mice. Experiments will test the hypothesis that TFAP2C establishes a trophoblast gene expression program by forming a regulatory complex with transcription factor TEAD4 and the HIPPO signaling protein YAP1. In Specific Aim 3 the importance of the TFAP2C-mediated mechanisms in mouse preimplantation embryos on subsequent postimplantation placental development will be determined. Experiments will test the hypothesis that precise regulation of Tfap2c during early development is essential for proper continuation of trophoblast progenitor development in postimplantation embryos. Lastly, Specific Aim 4 will elucidate the role of TFAP2C in human trophoblast lineage development. Proposed experiments will test the hypothesis that TFAP2C is required for trophoblast lineage formation and differentiation into functional syncytiotrophoblasts and extravillous trophoblasts. Taken together, results of the proposed studies will provide new insights into the regulatory role of TFAP2C in mouse and human trophoblast lineage development. The knowledge gained from these studies will be highly relevant to understanding the molecular basis of early embryonic loss and clinical reproductive disorders that are associated with abnormal placentation.

概括滋养层谱系的形成代表胎盘哺乳动物生命周期中的第一个分化事件。这个过程从植入前胚胎开始，并在植入后受孕时继续。准确建立滋养层谱系具有重大影响，包括发育停滞之前囊胚期、着床失败、早期流产和胎盘异常。拟议的研究之一是使用小鼠胚胎以及小鼠和人类胚胎干（ES）细胞作为模型系统来阐明控制滋养层谱系发育的转录机制。研究发现转录因子 AP-2γ (TFAP2C) 在触发和调节中具有新颖且关键的作用滋养层谱系发育的关键事件总体假设是 TFAP2C 是一个关键事件。小鼠和人类滋养层谱系形成的协调者，其在窗口期间的精确调节植入前发育对于特定目标 1 中的植入后胎盘发育至关重要。将确定 TFAP2C 在小鼠滋养层谱系形成中的作用实验将检验该假设。 TFAP2C 通过积极批评滋养层细胞的形成来诱导植入前胚胎的滋养层细胞命运具体目标 2 中的工作将定义 TFAP2C 诱导的分子机制。实验将检验 TFAP2C 所建立的假设。滋养层基因表达程序，通过与转录因子 TEAD4 形成调节复合物， HIPPO 信号蛋白 YAP1 在特定目标 3 中说明了 TFAP2C 介导机制的重要性。小鼠植入前胚胎对随后植入后胎盘发育的影响将被确定。实验将验证以下假设：早期发育过程中 Tfap2c 的精确调控对于最后，具体目标 4。将阐明 TFAP2C 在人类滋养层谱系发育中的作用拟议的实验将进行测试。假设 TFAP2C 是滋养层谱系形成和分化为功能性细胞所必需的合体滋养层和绒毛外滋养层合起来，所提出的研究结果将提供。关于 TFAP2C 在小鼠和人类滋养层谱系发育中的调节作用的新见解。从这些研究中获得的知识将与理解早期的分子基础高度相关。与胎盘异常相关的胚胎丢失和临床生殖障碍。