"Gdf6 gene expression and evolution in vertebrates"

“Gdf6 基因在脊椎动物中的表达和进化”

• 批准号: 7105193
• 负责人: DOUGLAS P MORTLOCK
• 金额: $ 1.87万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-17 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105193
• 关键词: Chordata; biochemical evolution; biological signal transduction; biotechnology; bone development; bone morphogenetic proteins; developmental genetics; evolution; gene expression; genetic enhancer element; genetic mapping; genetic promoter element; genetic regulatory element; genetically modified animals; in situ hybridization; laboratory mouse; molecular genetics; species difference; vertebrate embryology; zebrafish

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(申请人提供)：在胚胎模式形成和发育信号通路中发挥作用的基因可能包含许多基因组顺式调控序列，这些顺式调控序列必须正确发挥功能才能允许正常发育。对这类基因及其表达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以及人类先天性缺陷潜在遗传因素的理解。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成员之一，编码脊椎动物骨骼形态形成和发育所需的许多信号配体。在小鼠中，Gdf6对四肢、耳朵、头骨和脊柱骨骼关节、喉部以及可能包括心脏在内的其他结构的正常发育非常重要。在哺乳动物和鱼类的进化过程中，这些结构被不同地修改了，所以还不清楚Gdf6顺式调控序列在不同物种中保守到什么程度。然而，序列保守在多大程度上与保守的功能相关也是不清楚的，特别是关于非编码调控DNA。在这里，我们建议明确地解决Gdf6的同源基因在小鼠和斑马鱼骨骼发育过程中的表达和调控。使用转基因方法，他们将比较两个物种中功能相似和不同的Gdf6顺式调控元件的模块结构，并识别在发育中的肢体关节、颅缝、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型数据集，将单个顺式作用区的跨物种保护程度与调控功能的潜力相关联。这将为影响骨骼发育的调控序列提供一个大的、特征良好的基因组基因座的全面“扫描”。这些实验将为这个重要的信号通路基因在不同动物模型中的保守以及基因组序列在正常骨骼模式中所起的作用提供广泛的见解。