Comparative Genetics of the DiGeorge Syndrome Gene TBX1

迪乔治综合征基因 TBX1 的比较遗传学

• 批准号: 7544538
• 负责人: Raju S. Kucherlapati
• 金额: $ 29.48万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7544538
• 关键词: 22q11; Affect; Alleles; Biological Models; Branchial arch structure; Cardiovascular system; Cells; Classification; Complementary DNA; Defect; Development; DiGeorge Syndrome; Disease; Dysmorphology; Embryo; Etiology; Evolution; Face; Fishes; Gene Expression; Gene Expression Profiling; Gene Mutation; Gene Silencing; Generations; Genes; Genetic; Genetic Models; Genetic screening method; Genetically Engineered Mouse; Genomics; Genotype; Goals; Human; Human Chromosomes; Human Development; Immune system; In Situ Hybridization; Knockout Mice; Larva; Mediating; Methods; Modeling; Molecular Profiling; Mus; Mutant Strains Mice; Mutation; Neural Crest; Organ; Organism; Orthologous Gene; Pathway interactions; Patients; Pattern; Phenotype; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Role; Shprintzen syndrome; Staging; Syndrome; System; Testing; Tetrasomy; Time; Tissues; Transgenic Mice; Transgenic Organisms; Trisomy; Zebrafish; base; body system; cat eye syndrome; comparative; craniofacial; developmental disease; developmental genetics; gene discovery; genetic analysis; interest; knock-down; mutant; null mutation; overexpression; spatiotemporal; transcription factor

DESCRIPTION (provided by applicant): Velo cardio facial syndrome and DiGeorge syndrome (VCFS/DGS) are the most common human developmental disorders that result from haploinsufficiency. Most of the patients are hemizygous for 3 Mb deletion on human chromosome 22q11. Patients with VCFS/DGS have a number of abnormalities in tissues and organ systems that are derived from the neural crest. These include facial dysmorphology, cardiovascular defects, immune system defects and many others. Using the mouse as a model system the PIs have been able to show that mice that either overexpress or have reduced expression of Tbx1, a gene located in the deleted interval, have defects in many of the organs systems affected in VCFS/DGS patients. TBX1 encodes a transcription factor that is critical for normal neural crest development. Although information about the mechanisms of action of TBX1 is emerging, no systematic efforts to identify the pathways and networks in which TBX1 acts have been undertaken. The PIs propose to do so. TBX1 is highly conserved during evolution and mutations of this gene in the zebrafish, designated van gogh (vgo), develop phenotypes that are similar to those seen in VCFS/DGS patients. Based on these results, the PIs now propose a comparative genetics analysis of the TBX1 pathways and networks in zebrafish and mice. They propose to use gene expression profiling of normal and mutant zebrafish and mouse embryos at the appropriate developmental stages to discover genes whose expression patterns are altered as a result of reduction or absence of TBX1 protein. They will use whole mount in situ hybridization methods to examine the spatiotemporal patterns of expression of a large number of these genes in zebrafish. A subset will also be examined in Tbx1 mutant zebrafish and mice. Genes whose expression patterns match that of TBX1 or in appropriate cells and tissues will be subjected to genetic analysis in zebrafish through overexpression and morpholino-based knock-downs. If mutants for some of these genes are available, they will be examined alone and in combination with TBX1 mutants. In some cases the PIs will generate null and conditional mutant alleles in mice to examine their role in development. The combination of the use of zebrafish and mouse together with high throughput genetic and genomic approaches promise to provide rich information about the pathways and networks in which TBX1 operates.

描述（由申请人提供）：Velo Cardio面部综合征和Digeorge综合征（VCFS/DGS）是由单倍弥补导致的最常见的人类发育障碍。大多数患者对人类22q11的3 MB缺失进行半决赛。 VCF/DGS患者在组织和器官系统中有许多异常，这些异常是从神经rest中得出的。这些包括面部畸形，心血管缺陷，免疫系统缺陷等。使用小鼠作为模型系统，PIS能够表明，位于已删除间隔中的基因过表达或降低TBX1表达的小鼠在VCFS/DGS患者受影响的许多器官系统中都有缺陷。 TBX1编码一个对于正常神经rest发育至关重要的转录因子。尽管有关TBX1作用机制的信息正在出现，但没有系统地努力确定已经进行了TBX1行为的途径和网络。 PI建议这样做。在斑马鱼中，TBX1在进化过程中是高度保守的，并在斑马鱼中指定为van Gogh（VGO），开发与VCFS/DGS患者中发现的表型相似。基于这些结果，PIS现在提出了斑马鱼和小鼠中TBX1途径和网络的比较遗传学分析。他们建议在适当的发育阶段使用正常和突变体斑马鱼和小鼠胚胎的基因表达分析，以发现其表达模式因还原或缺乏TBX1蛋白而改变的基因。他们将使用整个安装原位杂交方法来检查斑马鱼中大量这些基因表达的时空模式。在TBX1突变斑马鱼和小鼠中也将检查子集。其表达模式与TBX1或适当细胞和组织中的表达模式相匹配的基因将通过过表达和基于Morpholino的敲除斑马鱼中进行遗传分析。如果这些基因中有一些突变体，则将单独检查它们并与TBX1突变体结合使用。在某些情况下，PI会在小鼠中产生无效的突变等位基因，以检查其在发育中的作用。使用斑马鱼和小鼠以及高吞吐量遗传和基因组方法的结合有望提供有关TBX1运行的途径和网络的丰富信息。