Brachyury-downstream gene networks in the notochord

脊索中的 Brachyury 下游基因网络

• 批准号: 8236501
• 负责人: ANNA DI GREGORIO
• 金额: $ 34.65万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236501
• 关键词: Binding; Binding Sites; Biological Models; Body Patterning; Brachyury protein; Chordata; Chordoma; Ciona intestinalis; Code; Comprehension; Data; Development; Embryo; Event; Evolution; Family; Gene Expression; Gene Expression Regulation; Gene Targeting; Gene Transfer Techniques; Generations; Genes; Genetic Transcription; Goals; Homologous Gene; Human; Immunotherapeutic agent; Investigation; Knowledge; Lead; Light; Malignant - descriptor; Marine Invertebrates; Mediating; Molecular; Mutation; Pathway interactions; Pattern; Phase; Play; Positioning Attribute; Process; Regulator Genes; Relative (related person); Research; Risk; Role; Sea; Spinal Dysraphism; Staging; Structure; Testing; Time; Transcription Coactivator; Transcriptional Regulation; Transgenic Organisms; Tumor-Derived; Urochordata; Vertebrates; activating transcription factor; ascidian; comparative; early onset; feeding; insight; interest; knock-down; loss of function; malformation; member; notochord; notochord development; novel; research study; secretory protein; small hairpin RNA; spine bone structure; transcription factor; tumorigenesis

DESCRIPTION (provided by applicant): The notochord plays a fundamental role in supporting and patterning the developing body plan in all chordate embryos. The transcription factor Brachyury is required for notochord formation and it is known to activate the transcription of numerous notochord genes in chordate embryos as different as sea squirts and humans. Mutations in the Brachyury coding region have been associated with vertebral malformations and increased risk of spina bifida. In addition, recent studies have indicated a direct association between the duplication of the human Brachyury locus and familial chordoma, a malignant notochord-derived tumor. The knowledge of the Brachyury-downstream gene cascade and, in particular, the identities of the transcription factors that act downstream of or in concert with Brachyury is still fragmentary. We use the basal chordate Ciona intestinalis (sea squirt), a simple yet informative vertebrate relative, as an accessible, fast-developing model system for identifying evolutionarily conserved transcriptional activators and for elucidating their hierarchical relationship with Ciona Brachyury (Ci-Bra). Our preliminary data, gathered from the comparative analysis of the structure and function of notochord cis-regulatory modules (CRMs) and from specific searches for notochord transcription factors evolutionarily conserved from Ciona to vertebrates, lead us to hypothesize that: 1) Ci-Bra controls part of its targets indirectly, via transcriptional intermediaries and 2) Ci-Bra controls part of its targets by acting synergistically with other transcription factors. We propose to characterize late-onset notochord transcription factors recently identified in our lab. Our main goals are to elucidate the role played by these factors in notochord development and to shed light on their hierarchical position within the Ci-Bra gene regulatory network. Our specific aims are: 1) Analyze the developmental role and targets of a newly identified transcription factor, and its relationship with Ci-Bra; 2) Identify the activators controlling the notochord CRMs identified in our lab and study their function in notochord development; 3) Characterize the role of Ci-Bra in late notochord differentiation through the analysis of one of its potential transcriptional intermediaries, Ci-XBP-1, and of its downstream targets. The broad scope of the proposed research is to exploit the experimental advantages of Ciona to rapidly gain basic insights into the mechanisms controlling gene expression in the notochord during development and evolution. In a wider perspective, this research aims to shed light on the molecular mechanisms employed by Brachyury to control its target genes, which, when compromised, are responsible for notochord malformations and notochord-derived tumorigenesis. Given the pervasive role of Brachyury in notochord formation in all chordates analyzed, it is likely that these findings will be applicable to vertebrates, including humans. PUBLIC HEALTH RELEVANCE: Brachyury is a transcription factor required for the formation of the notochord, a structure that supports and patterns the body of all chordates, including humans. In addition to its developmental role, Brachyury is also a specific marker, immunotherapeutic target and causative agent of chordomas, malignant notochord-derived tumors. The proposed studies use the Ciona embryo to rapidly shed light on Brachyury- downstream transcription factors, the way they are controlled by Brachyury, their function, and their target genes.

描述（由申请人提供）：脊索在支持和形成所有脊索动物胚胎发育中的身体计划方面发挥着基础作用。转录因子 Brachyury 是脊索形成所必需的，已知它可以激活脊索动物胚胎中许多脊索基因的转录，这些脊索动物胚胎与海鞘和人类不同。 Brachyury 编码区的突变与椎骨畸形和脊柱裂风险增加有关。此外，最近的研究表明，人类 Brachyury 基因座的重复与家族性脊索瘤（一种恶性脊索来源的肿瘤）之间存在直接关联。关于 Brachyury 下游基因级联的知识，特别是在 Brachyury 下游或与 Brachyury 协同作用的转录因子的身份仍然是零散的。我们使用基础脊索动物海鞘（海鞘）这种简单但信息丰富的脊椎动物近亲，作为一种易于使用、快速发展的模型系统，用于识别进化上保守的转录激活因子并阐明它们与海鞘（Ci-Bra）的层次关系。我们的初步数据来自对脊索顺式调控模块 (CRM) 结构和功能的比较分析，以及对从海鞘到脊椎动物进化上保守的脊索转录因子的具体搜索，使我们做出假设：1) Ci-Bra 控制通过转录中介间接控制其部分靶标；2) Ci-Bra 通过与其他转录因子协同作用来控制其部分靶标。我们建议表征我们实验室最近发现的晚发脊索转录因子。我们的主要目标是阐明这些因素在脊索发育中所起的作用，并阐明它们在 Ci-Bra 基因调控网络中的等级地位。我们的具体目标是： 1）分析新发现的转录因子的发育作用和靶点，及其与 Ci-Bra 的关系； 2) 确定我们实验室确定的控制脊索 CRM 的激活剂，并研究它们在脊索发育中的功能； 3) 通过分析 Ci-Bra 的潜在转录中介之一 Ci-XBP-1 及其下游靶标，表征 Ci-Bra 在晚期脊索分化中的作用。拟议研究的广泛范围是利用 Ciona 的实验优势，快速获得对发育和进化过程中脊索基因表达控制机制的基本了解。从更广泛的角度来看，这项研究旨在揭示 Brachyury 控制其靶基因的分子机制，当这些靶基因受到损害时，会导致脊索畸形和脊索衍生的肿瘤发生。鉴于 Brachyury 在所有分析的脊索动物脊索形成中的普遍作用，这些发现很可能适用于包括人类在内的脊椎动物。 公共卫生相关性：Brachyury 是形成脊索所需的转录因子，脊索是一种支撑和塑造包括人类在内的所有脊索动物身体的结构。除了其发育作用外，Brachyury 也是脊索瘤（恶性脊索源性肿瘤）的特异性标记物、免疫治疗靶点和致病因子。拟议的研究利用 Ciona 胚胎快速揭示 Brachyury 下游转录因子、Brachyury 控制它们的方式、它们的功能和它们的靶基因。