PATTERNING OF THE MESODERM BY T-BOX TRANSCRIPTION FACTORS

组成部分项目I：无尾的位置特定功能(NTL)：解开多效性 没有尾巴的突变体 主要调查者：大卫·乔纳·格伦瓦尔德；联合调查者：H·约瑟夫·约斯特 T-box基因编码相关的转录因子，调节机体各器官和区域的发育。 尸体。在该家族已知的20个成员中，有5个基因的突变与人类有关 先天性疾病。尽管进行了广泛的研究，但T盒突变在人类、小鼠、 或者斑马鱼是复杂的，人们对此知之甚少：多种组织类型都会受到影响，在任何情况下都不会 一个突变体的所有发育缺陷的统一细胞缺陷已被确定。我们建议 这种多效性是T-box基因的一个固有特征，需要去卷积才能理解细胞 T-box突变表型的基础。在这里，我们测试了两个假设，这可以解释TBox丢失的原因 转录因子经常导致多种细胞类型缺陷。首先，我们建议 单个T-box转录因子在不同的区域有不同的下游靶基因集 胚胎，从而解释了T-box突变体的反复多效性。第二，我们提出了一个因素 有助于T-box因子功能多样化的是与额外的T-box转录的相互作用 各种因素。因此，一个T-box转录因子的缺失会影响其他T-box因子的功能 在发育领域中表达。 组件项目I分析了无尾控制的下游功能，斑马鱼的同源基因 脊椎动物brachyury/tj-box基因，没有尾巴在整个中胚层表达，并需要 脊索、后中胚层和尾器库普弗氏囊泡的发育。的目标 组分项目I是：1)鉴定No Tail蛋白的位置特异性转录活性；2) 分析与其他T-box因素的相互作用如何有助于No Tail的特定位置活动； 3)验证NTL的不同直接靶基因执行独立的位置/组织特异性的想法 无尾的发育功能。

Component Project I: Position-Specific Functions of no tail (ntl): Untangling the Pleiotropy of the no tail Mutant Principal Investigator: David Jonah Grunwald; Co-Investigator: H. Joseph Yost T-box genes encode related transcription factors that regulate development of organs and regions of the body. Of the >20 known members of the family, mutations in five genes have been linked to human congenital disorders. Despite extensive study, the phenotypes caused by T-box mutations in humans, mice, or zebrafish are complex and poorly understood: multiple tissue types are affected, and in no case has a unifying cellular defect been identified that accounts for all developmental defects of a mutant. We propose that pleiotropy is an intrinsic feature of T-box genes that needs to be deconvoluted to understand the cellular basis of T-box mutant phenotypes. Here we test two hypotheses that that would account for why loss of a Tbox transcription factor frequently results in a multiplicity of cell type defects. First, we propose that individual T-box transcription factors have different sets of downstream target genes in different regions of the embryo, thus explaining the recurrent pleiotropy of T-box mutants. Second, we propose that one factor that contributes to diversification of T-box factor function is interaction with additional T-box transcription factors. Hence loss of one T-box transcription factor affects the function of other T-box factors that continue to be expressed in a developmental field. Component Project I analyzes the downstream functions controlled by no tail, the zebrafish orthologue of the vertebrate Brachyury/TJ-box gene, no tail is expressed throughout the mesoderm and required for development of the notochord, the posterior mesoderm, and the tail organ, Kupffer's Vesicle. The goals of Component Project I are: 1) identify the position-specific transcription activities of the No Tail protein; 2) analyze how interactions with additional T-box factors contribute to the position-specific activities of No Tail; and 3) test the idea that distinct direct target genes of NTL carry out independent position/tissue-specific developmental functions of no tail.