Fibulin-1 Regulation of the DiGeorge Syndrome Pathogenesis Pathway

Fibulin-1 对 DiGeorge 综合征发病机制的调节

• 批准号: 7994829
• 负责人: WILLIAM SCOTT ARGRAVES
• 金额: $ 36.88万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7994829
• 关键词: 22q11; Affect; Apoptosis; Area; Birth; Boxing; Branchial arch structure; Cardiac; Cell Proliferation; Cell physiology; Cells; Cephalic; Congenital Abnormality; Congenital Heart Defects; Cranial Nerves; DNA Microarray Chip; Development; DiGeorge Syndrome; Embryo; Etiology; Exhibits; Extracellular Matrix Proteins; Frequencies; Gene Silencing; Genetic; Gland; Glossopharyngeal nerve structure; Growth Factor; Heart; Human; Immigration; Lead; Maps; Mediating; Mesenchyme; Microarray Analysis; Molecular; Mus; Myocardium; Neural Crest Cell; Neural tube; Parathyroid gland; Pathogenesis; Pathway interactions; Pattern; Phenotype; Phosphotransferases; Play; Primordium; Proteoglycan; Proteolysis; Pulmonary artery structure; Regulation; Research; Research Design; Role; Signal Pathway; Somites; Structure; Testing; Thymus Gland; Thyroid Gland; Tissues; Ventricular; bone; cell behavior; cell motility; craniofacial; cranium; fibulin 1; hindbrain; insight; malformation; migration; novel; public health relevance; stem; transcription factor; versican

DESCRIPTION (provided by applicant): New findings from targeted gene inactivation studies in mice reveal that the extracellular matrix protein fibulin-1 (Fbln1) is required for normal development of the cardiac outflow tract (OFT), pharyngeal glands, cranial nerves and bones of the skull. The developmental anomalies displayed by mice deficient in Fbln1 recapitulate many of the anomalies associated with 22q11 deletion/DiGeorge syndrome (DGS), which occurs with a frequency of 1:4000 human births. The similarity in phenotypes between Fbln1-deficient mice and DGS humans suggests that Fbln1, although located outside of the 22q11 deletion region, is a modifier of the pathway that is dysfunctional in DGS. The molecular pathway of DGS has not been fully elucidated. Key components are the transcription factor Tbx1, Fgf8 and intermediates of the Fgf8 signaling pathway. Several lines of evidence support the hypothesis that Fbln1 regulates this pathway. DNA microarray analysis indicates that Fbln1 is required for expression of forkhead box transcription factors that regulate expression of both Tbx1 and Fgf8 in pharyngeal arch regions including the secondary heart field (SHF). qPCR analysis shows that Tbx1 expression is significantly decreased in pharyngeal arch-containing tissues from Fbln1 null embryos. We also find that Fbln1 interacts with Fgf8 and inhibits Fgf8-mediated activation of the Map kinase-signaling pathway. These observations together with findings that Fbln1 is expressed along pathways of NCC migration, that it can act as a regulator of cell guidance and motility and that it interacts and modulates proteolysis of the proteoglycan versican, a regulator of NCC migration, lead to the following hypothesis: Fbln1 is a key component of the mechanism by which Fgf8 influences NCC-dependent development of the pharyngeal arch and the formation of derivative structures including the OFT, pharyngeal glands and craniofacial structures. To test this hypothesis and gain mechanistic understanding there are three specific aims: 1) Define the effects of Fbln1 on the Fgf8 signaling pathway; 2) Identify genetic interactions between Fbln1 and Tbx1 and between Fbln1 and versican; and 3) Define the role of Fbln1 in controlling NCC proliferation and guidance. Findings from this experimentation are expected to lead to new insights into the mechanism by which Fbln1 guides the normal development of the cardiac OFT, great vessels, cranium and pharyngeal glands and to contribute to an understanding of the etiology of congenital defects involving these tissues. Public Health Relevance: This research seeks to gain a mechanistic understanding of the developmental anomalies (including heart defects) associated with DiGeorge syndrome (DGS), which occurs with a frequency of one in 4000 human births. The proposed studies are designed to determine the role of the extracellular matrix protein, fibulin-1, in regulating the behaviors of cells (neural crest cells) that contribute to the formation of tissues affected in DGS. A novel direction for the research stems from our discovery that fibulin-1 regulates the activity of Fgf8, a growth factor implicated as a key component of the pathway that is dysfunctional in DGS.

描述（由申请方提供）：小鼠靶向基因失活研究的新发现表明，细胞外基质蛋白质fibulin-1（Fbln 1）是心脏流出道（OFT）、咽腺、颅神经和颅骨正常发育所必需的。Fbln 1缺陷小鼠表现出的发育异常概括了许多与22 q11缺失/DiGeorge综合征（DGS）相关的异常，该综合征以1：4000的人类出生频率发生。Fbln 1缺陷小鼠和DGS人类之间表型的相似性表明，Fbln 1虽然位于22 q11缺失区之外，但却是DGS中功能失调的通路的修饰剂。DGS的分子途径尚未完全阐明。关键组分是转录因子Tbx 1、Fgf 8和Fgf 8信号通路的中间体。有几条证据支持Fbln 1调节这一通路的假设。DNA微阵列分析表明，Fbln 1是需要表达的叉头盒转录因子，调节表达的Tbx 1和Fgf 8在咽弓地区，包括第二心脏领域（SHF）。qPCR分析显示，Tbx 1表达在来自Fbln 1缺失胚胎的含咽弓的组织中显著降低。我们还发现，Fbln 1与Fgf 8相互作用，抑制Fgf 8介导的激活的地图激酶信号通路。这些观察结果连同Fbln 1沿NCC迁移的沿着途径表达、其可充当细胞引导和运动的调节剂以及其相互作用并调节蛋白聚糖多功能蛋白聚糖（NCC迁移的调节剂）的蛋白水解的发现，导致以下假设：Fbln 1是Fgf 8影响NCC机制的关键组分。咽弓的依赖性发育以及包括OFT、咽腺和颅面结构在内的衍生结构的形成。为了检验这一假设并获得机制理解，有三个具体目标：1）定义Fbln 1对Fgf 8信号传导途径的影响; 2）鉴定Fbln 1和Tbx 1之间以及Fbln 1和多功能蛋白聚糖之间的遗传相互作用;和3）定义Fbln 1在控制NCC增殖和指导中的作用。这项实验的发现有望为Fbln 1指导心脏OFT、大血管、颅骨和咽腺正常发育的机制提供新的见解，并有助于了解涉及这些组织的先天性缺陷的病因。公共卫生相关性：这项研究旨在获得与DiGeorge综合征（DGS）相关的发育异常（包括心脏缺陷）的机械理解，该综合征的发生频率为4000人中的一人。拟议的研究旨在确定细胞外基质蛋白fibulin-1在调节细胞（神经嵴细胞）行为中的作用，这些细胞有助于DGS受影响组织的形成。一个新的研究方向源于我们的发现，fibulin-1调节Fgf 8的活性，Fgf 8是一种生长因子，是DGS中功能失调的途径的关键组分。