"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：
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
项目类别：
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

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扮演角色的基因可能包含许多基因组顺式调节序列，这些序列必须正常运行以允许正常发育。对控制其表达的这种基因和调节序列的研究将进一步了解我们对人类基因组调节性DNA在人类发育中的功能以及人类先天性缺陷的遗传因素的功能。因此，PI建议分析脊椎动物GDF6基因的调节结构。 GDF6是BMP信号因子基因家族的成员，它编码脊椎动物骨骼模式和发育所需的许多信号配体。在小鼠中，GDF6对于肢体，耳朵，头骨和脊柱骨骼关节，喉部以及包括心脏在内的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经过了不同的修饰，因此尚不清楚在多大程度上在多大程度上保守了跨物种的gdf6顺式调节序列。但是，序列保护通常与保守功能相关的程度尚不清楚，尤其是在非编码调节DNA方面。在这里，我们建议在小鼠和斑马鱼骨骼发育过程中明确地解决GDF6（一个重要的骨骼图案基因）直系同源物的表达和调节。使用转基因方法，它们将比较这两个物种中功能相似和不同的GDF6顺式调节元件的模块化结构，并确定在发育中的肢体关节，颅骨缝合线，颌骨和骨头和喉咙结构中控制GDF6表达的新型远程基因组调节元件。 PI通过测试大量候选调节序列的大量数据集，将单个顺式作用区域中的跨物种保护程度与潜在的调节功能相关联。这将为影响骨骼发育的调节序列提供全面的大型，良好的基因组基因座的“扫描”。这些实验将提供有关在不同动物模型中这种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起作用的作用的广泛见解。