Brachyury-downstream gene networks in the notochord

脊索中的 Brachyury 下游基因网络

• 批准号: 8629771
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629771
• 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.

描述(由申请人提供)：脊索在所有脊索胚胎中支持和形成发育的身体计划中起着基本的作用。转录因子brachyury是脊索形成所必需的，已知它可以激活脊索胚胎中许多脊索基因的转录，就像海鞘和人类一样不同。短臂编码区的突变与脊椎畸形和脊柱裂风险增加有关。此外，最近的研究表明，人类短脊索基因的重复与家族性脊索瘤(一种恶性脊索起源肿瘤)之间存在直接联系。人们对短尾藻下游基因级联的了解，尤其是短尾藻下游或与短尾藻协同作用的转录因子的身份识别，仍然是零散的。我们使用一种简单但信息量丰富的脊椎动物近亲--海鞘作为一个可访问的、快速发展的模型系统来识别进化上保守的转录激活因子，并阐明它们与短吻海鞘(Ciona brachyury，Ci-Bra)的等级关系。我们的初步数据来自对脊索顺式调节模块(CRM)结构和功能的比较分析，以及对从Ciona到脊椎动物进化上保守的Notochord转录因子的特定搜索，这些数据使我们假设：1)Ci-Bra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控制其部分靶标。我们建议对最近在我们实验室发现的迟发性脊索转录因子进行特征分析。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位置。我们的具体目标是：1)分析一个新发现的转录因子的发育作用和靶标，以及它与Ci-Bra的关系；2)鉴定我们实验室中发现的控制脊索CRM的激活子，并研究它们在脊索发育中的功能；3)通过分析Ci-Bra潜在的转录中介之一Ci-XBP-1及其下游靶标，来表征Ci-Bra在脊索晚期分化中的作用。拟议的研究范围广泛，旨在利用Ciona的实验优势，迅速获得对脊索发育和进化过程中基因表达控制机制的基本见解。从更广泛的角度来看，这项研究旨在阐明短臂猿控制其靶基因的分子机制，当受到损害时，这些基因会导致脊索畸形和脊索衍生的肿瘤发生。考虑到在所有被分析的脊索动物中，短脊索在脊索形成中的普遍作用，这些发现很可能适用于脊椎动物，包括人类。