FIBULIN-1 MAINTENANCE OF THE FGF8-DEPENDENT PROXIMAL MANDIBULAR GENETIC PROGRAM

FIBULIN-1 维持 FGF8 依赖的近端下颌遗传程序

• 批准号: 8360489
• 负责人: Marion A. Cooley
• 金额: $ 7.03万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-09-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360489
• 关键词: Binding; Binding Sites; Centers of Research Excellence; Cephalic; Development; Differentiation and Growth; Extracellular Matrix Proteins; FGF8 gene; Feedback; Fibroblast Growth Factor 8; Funding; Genes; Genetic Programming; Grant; Knockout Mice; Lead; Light; Maintenance; Mandible; Maps; Modeling; Morphogenesis; Mus; National Center for Research Resources; Neural Crest Cell; Oral health; Pathway interactions; Phosphotransferases; Principal Investigator; Research; Research Infrastructure; Resources; Role; Signal Transduction; Source; South Carolina; Structure; System; Testing; Transcriptional Activation; United States National Institutes of Health; cost; craniofacial; fibulin 1; homeodomain; malformation; novel; response; transcription factor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The extracellular matrix protein, fibulin-1 (Fbln1), has been shown to be critical for the development of craniofacial structures. Indeed, the spectrum of malformations observed in Fbln1 null mice are consistent with Fbln1 having a role in the growth and differentiation of cranial neural crest cells (CNCs) which contribute to the morphogenesis of structure derived from the first brachial arch (BA1) e.g., the mandible. Pathways key to the growth and differentiation of CNCs have not been fully established, however a number of genes including fibroblast growth factor 8 (Fgf8) are known to be critical. The fact that mice deficient in Fbln1 share some overlapping mandibular malformations with mice deficient in Fgf8, together with evidence that Fbln1 binds Fgf8 has lead us to hypothesize that Fbln1 may be involved in promoting Fgf8 signaling in BA1. A key aspect of Fgf8 signaling in BA1 is the proximal activation of Fgf8 response genes. One such gene is the homeodomain transcription factor, Barx1 which is critical for mandibular formation 12 and activates Fbln1 expression 2. We have found that Fbln1-deficient mice show reduced Barx1 expression. Furthermore, we have identified two potential Barx1 binding sites in the Fbln1 gene. In light of this information, we propose a novel regulatory model in which Fbln1 promotes Fgf8-FgfR signaling in CNCs that leads to the expression of Barx1 and the transcriptional activation of the Fbln1 gene, thus creating a positive feedback loop. We speculate that this positive feedback system promotes the proliferation and differentiation of CNCs within BA1. To test this model there are three specific aims: 1) to determine whether Fbln1 deficiency leads to suppression of Fgf8 signaling (i.e., Map kinase pathway intermediates) in the BA1, 2) to determine whether Fbln1 deficiency leads to suppression of Fgf8 response genes (i.e., Barx1, Gsc, Spry1/2 and Lhx6) required for mandibular morphogenesis, and 3) to determine if Fbln1 is regulated transcriptionally by Barx1.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 细胞外基质蛋白，fibulin-1（Fbln 1），已被证明是至关重要的颅面结构的发展。实际上，在Fbln 1缺失小鼠中观察到的畸形谱与Fbln 1在颅神经嵴细胞（CNC）的生长和分化中起作用一致，所述CNC有助于源自第一臂弓（BA 1）的结构的形态发生，例如，下颌骨CNC生长和分化的关键途径尚未完全建立，但已知包括成纤维细胞生长因子8（Fgf 8）在内的许多基因是关键的。Fbln 1缺陷的小鼠与Fgf 8缺陷的小鼠共享一些重叠的下颌畸形的事实，以及Fbln 1结合Fgf 8的证据，使我们假设Fbln 1可能参与促进BA 1中的Fgf 8信号传导。BA 1中Fgf 8信号传导的一个关键方面是Fgf 8应答基因的近端激活。一个这样的基因是同源域转录因子Barx 1，其对下颌骨形成至关重要12并激活Fbln 1表达2。我们发现Fbln 1缺陷小鼠表现出Barx 1表达减少。此外，我们已经确定了Fbln 1基因中的两个潜在的Barx 1结合位点。根据这些信息，我们提出了一种新的调控模型，其中Fbln 1促进CNCs中的Fgf 8-FgfR信号传导，导致Barx 1的表达和Fbln 1基因的转录激活，从而形成正反馈环。我们推测，这种正反馈系统促进BA 1内CNCs的增殖和分化。为了测试该模型，有三个具体目的：1）确定Fbln 1缺陷是否导致Fgf 8信号传导的抑制（即，图激酶途径中间体），以确定Fbln 1缺乏是否导致Fgf 8应答基因的抑制（即，Barx 1、Gsc、Spry 1/2和Lhx 6），以及3）确定Fbln 1是否受Barx 1的转录调控。