TEAD4 and Trophoblast Lineage

TEAD4 和滋养层谱系

基本信息

批准号：
8583638
负责人：
Soumen Paul
金额：
$ 18.88万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8583638
关键词：
Address Affect Biological Models Blood Vessels CDX2 gene Cell Lineage Cells Cessation of life Chromatin Defect Development Disease Ectoderm Embryo Failure Fetal Growth Retardation First Pregnancy Trimester Foundations Gases Gene Expression Gene Expression Profile Gene Targeting Genes Goals Hormones Human Impairment Inner Cell Mass Knockout Mice Lead Mediating Molecular Mothers Mus Nutrient Organ Pathway interactions Placenta Placentation Population Pre-Eclampsia Pregnancy Pregnancy loss Premature Birth Public Health Rattus Retinal Cone Risk Rodent Specific qualifier value Spontaneous abortion Staging Stem cells Testing Tissues blastocyst chromatin immunoprecipitation deep sequencing genome-wide insight knockout gene member mouse development mouse model natural Blastocyst Implantation preimplantation progenitor programs public health relevance stem cell population transcription factor trophoblast

项目摘要

DESCRIPTION (provided by applicant): Trophoblast cell lineages build the functional units of the organ, the placenta and are important for the anchorage of the embryo to the mother, for establishing a vascular connection for nutrient and gas transport to the embryo, and expression of hormones that are required for the successful progression of pregnancy. Defective development of the trophoblast cell lineages leads to either failure of embryo implantation or pregnancy associated disorders like preeclampsia. Thus it is important to understand molecular pathways that regulate development of the trophoblast cell lineages. The origination of trophoblast cell lineages starts with the establishment of the trophectoderm (TE), one of the first two cell lineages that are specified during preimplantation mammalian development. Gene knockout studies in mice showed that TEAD4, a member of TEA-domain containing transcription factors, is the master orchestrator of the TE-specific transcriptional program. TEAD4-null embryos do not mature to the blastocyst stage and lack expression of master regulators of trophoblast development, like CDX2, and GATA3. Interestingly, although TEAD4 specifically regulates TE/trophoblast-specific gene expression during early mouse development, direct targets of TEAD4 have not been identified in the TE or in trophoblast progenitors of the developing placenta. Furthermore, functional importance of TEAD4 during trophoblast lineage development after embryo implantation has not been tested. Thus, the molecular mechanisms by which TEAD4 regulates trophoblast lineage development are poorly understood. The goal of this proposal is to define molecular mechanisms by which TEAD4 selectively orchestrate a trophoblast stem cell-specific transcriptional program. Two specific aims are proposed; in aim 1, we will define global TEAD4-dependent transcriptional network in trophoblast cells. Using both mouse and rat as model systems, we will test the hypothesis that TEAD4 regulates a core TSC-specific transcriptional network within the TE of a preimplantation embryo. We will use chromatin immunoprecipitation along with genome wide sequencing (ChIP-Seq) to identify TEAD4 target genes in trophoblast cells and to define a global TEAD4-dependent, trophoblast-specific transcriptional network. In aim 2, we will determine importance of TEAD4 in postimplantation trophoblast lineage development. We will test the hypothesis that similar to preimplantation TE-lineage development, TEAD4 function is also important to maintain expression of TSC-specific genes within the trophoblast progenitors of the developing placenta and impairment of TEAD4 function after embryo implantation will negatively affect development of trophoblast lineages.

描述（由申请人提供）：滋养层细胞谱系构建器官、胎盘的功能单位，对于胚胎与母体的锚定、建立营养和气体向胚胎运输的血管连接以及表达妊娠成功进展所需的激素。滋养层细胞谱系的发育缺陷会导致胚胎植入失败或妊娠相关疾病，例如先兆子痫。因此，了解调节滋养层细胞谱系发育的分子途径非常重要。滋养层细胞谱系的起源始于滋养外胚层 (TE) 的建立，滋养外胚层是最早的细胞之一。在植入前哺乳动物发育过程中指定的两种细胞谱系。小鼠基因敲除研究表明，TEAD4 是含有转录因子的 TEA 结构域的成员，是 TE 特异性转录程序的主要协调者。 TEAD4 缺失的胚胎不会成熟到囊胚阶段，并且缺乏滋养层发育的主调节因子（如 CDX2 和 GATA3）的表达。有趣的是，尽管 TEAD4 在小鼠早期发育过程中特异性调节 TE/滋养层特异性基因表达，但在 TE 或发育中的胎盘的滋养层祖细胞中尚未发现 TEAD4 的直接靶标。此外，TEAD4 在胚胎植入后滋养层谱系发育过程中的功能重要性尚未得到测试。因此，人们对 TEAD4 调节滋养层谱系发育的分子机制知之甚少。该提案的目标是定义 TEAD4 选择性协调滋养层干细胞特异性转录程序的分子机制。提出了两个具体目标；在目标 1 中，我们将定义滋养层细胞中全局 TEAD4 依赖性转录网络。使用小鼠和大鼠作为模型系统，我们将测试 TEAD4 调节植入前胚胎 TE 内的核心 TSC 特异性转录网络的假设。我们将使用染色质免疫沉淀和全基因组测序 (ChIP-Seq) 来识别滋养层细胞中的 TEAD4 靶基因，并定义一个全局 TEAD4 依赖性、滋养层特异性转录网络。在目标 2 中，我们将确定 TEAD4 在植入后滋养层谱系发育中的重要性。我们将检验以下假设：与植入前 TE 谱系发育类似，TEAD4 功能对于维持发育中胎盘的滋养层祖细胞内 TSC 特异性基因的表达也很重要，并且胚胎植入后 TEAD4 功能受损将对滋养层谱系的发育产生负面影响。