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"Gdf6 gene expression and evolution in vertebrates"

“Gdf6 基因在脊椎动物中的表达和进化”

基本信息

批准号：
7929967
负责人：
DOUGLAS P MORTLOCK
金额：
$ 5.94万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2010-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7929967
关键词：
Address Animal Model Architecture Bone Morphogenetic Proteins Branchial arch structure Cartilage Comparative Study Complex Congenital Abnormality Conserved Sequence Control Locus DNA DNA Sequence Data Set Development Digit structure Ear Elements Embryo Embryonic Pattern Specification Engineering Enhancers Evolution Fishes Gene Expression Gene Family Genes Genetic Genetic Transcription Genomics Health Heart Human Human Development In Situ Hybridization Individual Intercistronic Region Jaw Joints LacZ Genes Larynx Ligands Limb Development Limb structure Link Location Mammals Maps Modeling Molecular Morphology Mus Names Nucleic Acid Regulatory Sequences Orthologous Gene Pattern Play Protein Family Radar Regulation Regulator Genes Regulatory Element Reporter Research Personnel Role Scanning Sequence Analysis Sequence Homology Signal Pathway Signal Transduction Signaling Molecule Signaling Pathway Gene Site Skeletal Development Structure Surgical sutures Testing Tissues Transgenic Mice Transgenic Organisms Vertebral column Vertebrates Zebrafish bone comparative cranium insight limb bone malformation member middle ear mouse development novel paralogous gene programs promoter research study skeletal

项目摘要

DESCRIPTION (provided by applicant): Genes that play roles in embryonic pattern formation and developmental signaling pathways are likely to contain many genomic cis-regulatory sequences that must function properly to allow normal development. The study of such genes and regulatory sequences that control their expression will further our understanding of the function of genomic regulatory DNA in human development and of genetic factors underlying congenital defects in humans. Therefore, the PIs propose to analyze the regulatory architecture of the vertebrate Gdf6 genes. Gdf6 is a member of the BMP signaling factor gene family, which encodes many signaling ligands required for vertebrate skeletal patterning and development. In mouse, Gdf6 is important for normal development of limb, ear, skull and spine skeletal joints, the larynx, and potentially other structures including the heart. These structures have been differently modified during evolution of mammals and fish, so it is unclear to what extent Gdf6 cis-regulatory sequences are conserved across species. However, the extent to which sequence conservation generally correlates with conserved function is also unclear, especially with regard to noncoding regulatory DNA. Here we propose to definitively address the expression and regulation of orthologs for Gdf6, an important skeletal patterning gene, during mouse and zebrafish skeletal development. Using transgenic approaches, they will compare the modular structure of functionally similar and dissimilar Gdf6 cis-regulatory elements in both species, and identify novel long-range genomic regulatory elements controlling Gdf6 expression in developing limb joints, skull sutures, jaw and ear bones, and laryngeal structures. The PIs will correlate the degree of cross-species conservation in individual cis-acting regions with potential for regulatory function, by testing a large data set of candidate regulatory sequences. This will provide a comprehensive "scan" of a large, well-characterized genomic locus for regulatory sequences that impact skeletal development. These experiments will provide extensive insights into the conservation of this important signaling pathway gene in different animal models and the role genomic sequences play in normal skeletal patterning.

描述（由申请人提供）：在胚胎模式形成和发育信号通路中起作用的基因可能包含许多基因组顺式调控序列，这些序列必须正常运行才能允许正常发育。对这些基因和控制其表达的调控序列的研究将进一步加深我们对基因组调控DNA在人类发育中的功能和人类先天性缺陷的遗传因素的理解。因此，pi建议分析脊椎动物Gdf6基因的调控结构。Gdf6是BMP信号因子基因家族的一员，该基因家族编码许多脊椎动物骨骼模式和发育所需的信号配体。在小鼠中，Gdf6对肢体、耳朵、头骨和脊柱骨骼关节、喉部以及包括心脏在内的潜在其他结构的正常发育很重要。这些结构在哺乳动物和鱼类的进化过程中发生了不同的修饰，因此尚不清楚Gdf6顺式调控序列在物种间的保守程度。然而，序列保守通常与保守功能相关的程度也不清楚，特别是关于非编码调控DNA。在这里，我们提出明确地解决Gdf6同源物的表达和调控，一个重要的骨骼模式基因，在小鼠和斑马鱼骨骼发育。利用转基因方法，他们将比较两个物种中功能相似和不相似的Gdf6顺式调控元件的模块化结构，并确定在肢体关节、颅骨缝合线、颌骨和耳骨以及喉部结构中控制Gdf6表达的新的远程基因组调控元件。pi将通过测试候选调控序列的大量数据集，将单个顺式作用区域的跨物种保护程度与潜在的调控功能联系起来。这将为影响骨骼发育的调控序列提供一个大的、特征良好的基因组位点的全面“扫描”。这些实验将为不同动物模型中这一重要信号通路基因的保护以及基因组序列在正常骨骼模式中的作用提供广泛的见解。