"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: 7342122
• 负责人: DOUGLAS P MORTLOCK
• 金额: $ 31.57万
• 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/7342122
• 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; Disruption; 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; Localized; Location; Mammals; Maps; Modeling; Molecular; Morphology; Mus; Names; Nucleic Acid Regulatory Sequences; Orthologous Gene; Pattern; Play; Protein Family; Radar; Range; Regulation; Regulator Genes; Regulatory Element; Reporter; Research Personnel; Role; Role playing therapy; Scanning; Sequence Analysis; Sequence Homology; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Pathway Gene; Site; Skeletal Development; Skeletal system; Structure; Surgical sutures; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Vertebral column; Vertebrates; Zebrafish; bone; comparative; cranium; insight; limb bone; malformation; member; middle ear; novel; paralogous gene; programs; promoter; research study

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发挥作用的基因可能包含许多基因组顺式调控序列，这些序列必须正常发挥作用以允许正常发育。对此类基因和控制其表达的调控序列的研究将进一步了解基因组调控 DNA 在人类发育中的功能以及人类先天性缺陷的遗传因素。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，该家族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 对于四肢、耳朵、头骨和脊柱骨骼关节、喉以及包括心脏在内的其他潜在结构的正常发育非常重要。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，序列保守性与保守功能的关联程度尚不清楚，特别是对于非编码调控 DNA。在这里，我们建议明确解决 Gdf6（一种重要的骨骼模式基因）直向同源物在小鼠和斑马鱼骨骼发育过程中的表达和调节。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结构，并确定控制发育中的四肢关节、颅骨缝、颌骨和耳骨以及喉结构中 Gdf6 表达的新型远程基因组调控元件。通过测试候选调控序列的大数据集，PI 将把各个顺式作用区域的跨物种保守程度与调控功能的潜力联系起来。这将对大型、特征明确的基因组位点进行全面的“扫描”，以寻找影响骨骼发育的调控序列。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发挥的作用提供广泛的见解。