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）：脊索在支持和模仿所有脉管胚胎中发展的身体计划方面起着基本作用。脊索形成需要转录因子Brachyury，并且众所周知，它可以激活与海洋喷射和人类一样不同的静脉胚胎中众多脊索基因的转录。 Brachyury编码区域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，人胸骨基因座的重复与家族性脊髓瘤（一种恶性脊索衍生的肿瘤）之间存在直接关联。对Brachyury-Downstream基因级联反应的了解，尤其是在下游或与Brachyury一起进行的转录因子的身份仍然是零碎的。我们将基底弦核Ciona Intestinalis（Sea Squirt）（Sea Squirt）（Sea Squirt）（一种简单但有益的脊椎动物亲戚）作为一种易于访问，快速开发的模型系统，用于识别进化上保守的转录激活剂并阐明其与Ciona Brachyury（Ci-i-Bra）的层次关系。我们的初步数据是从对脊索调节模块（CRM）的结构和功能的比较分析中收集的，以及从对脊索转录因子的特定搜索从ciona到脊椎动物的进化保守的，导致我们假设我们通过其靶标的COI-BRA控制范围，其靶标的ci-BRA控制，其靶标的CII-CII-2）CIII-2）CIII-2）与其他转录因子协同作用。我们建议表征最近在我们的实验室中发现的晚期脊索转录因子。我们的主要目标是阐明这些因素在脊索发展中所起的作用，并阐明其在CI-BRA基因调节网络中的层次位置。我们的具体目的是：1）分析新鉴定的转录因子的发育作用和靶标及其与CI-BRA的关系； 2）确定控制我们实验室中识别的脊索CRM的激活剂，并研究其在努力训练中的功能； 3）通过分析其潜在的转录中介机构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，以迅速获得对控制基因表达在发育和进化过程中基因表达的机制的基本见解。从更广泛的角度来看，这项研究旨在阐明Brachyury用于控制其靶基因的分子机制，该基因在受到损害的情况下，该基因造成了诺修畸形和诺修多衍生的肿瘤发生。鉴于Brachyury在分析的所有和弦中的脊索形成中的普遍作用，这些发现可能适用于包括人类在内的脊椎动物。 公共卫生相关性：Brachyury是脊索形成所需的转录因素，该结构支持和模式，包括包括人类在内的所有和弦的身体。除了其发育作用外，Brachyury还是特定的标记，免疫治疗靶标和脊髓瘤，恶性脊索衍生的肿瘤的病因。拟议的研究使用ciona胚胎快速阐明了胸膜下游的转录因子，即它们的功能，其功能和目标基因的控制方式。