FGF in Sensory System Development

FGF 在感觉系统开发中的应用

• 批准号: 7915260
• 负责人: Olivia Mary Bermingham-McDonogh
• 金额: $ 41.5万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915260
• 关键词: Address; Adult; Biological; Cell Differentiation process; Cells; Cochlea; Cochlear duct; Computer Systems Development; Congenital Disorders; Development; Employee Strikes; FGF20 gene; FGF8 gene; FGFR1 gene; FGFR3 gene; Failure; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Funding; Genes; Grant; Hair Cells; In Vitro; Inner Hair Cells; Investigation; Knockout Mice; Lateral; Lead; Ligands; Mediating; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Natural regeneration; Notch Signaling Pathway; Organ of Corti; Outer Hair Cells; Pathway interactions; Pattern; Phase; Phenotype; Pillar Cell; Play; Process; Regulation; Reporting; Role; Sensory; Series; Signal Transduction; Sorting - Cell Movement; Specific qualifier value; Staging; Supporting Cell; System; Techniques; Testing; Time; Transgenic Organisms; deafness; homeodomain; in vivo; mutant; notch protein; progenitor; research study; sensory system; therapy design; transcription factor; Address; Adult; Biological; Cell Differentiation process; Cells; Cochlea; Cochlear duct; Computer Systems Development; Congenital Disorders; Development; Employee Strikes; FGF20 gene; FGF8 gene; FGFR1 gene; FGFR3 gene; Failure; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Funding; Genes; Grant; Hair Cells; In Vitro; Inner Hair Cells; Investigation; Knockout Mice; Lateral; Lead; Ligands; Mediating; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Natural regeneration; Notch Signaling Pathway; Organ of Corti; Outer Hair Cells; Pathway interactions; Pattern; Phase; Phenotype; Pillar Cell; Play; Process; Regulation; Reporting; Role; Sensory; Series; Signal Transduction; Sorting - Cell Movement; Specific qualifier value; Staging; Supporting Cell; System; Techniques; Testing; Time; Transgenic Organisms; deafness; homeodomain; in vivo; mutant; notch protein; progenitor; research study; sensory system; therapy design; transcription factor

DESCRIPTION (provided by applicant): The development of the organ of Corti is a tightly regulated process, in which a small "prosensory" domain of the cochlear duct is sorted into various types of hair cells and support cells. Over the past five years, a model of this process has emerged, primarily through analysis of mice with mutations in developmentally expressed genes. The prosensory region, defined by p27 expression, is specified by the Notch pathway ligand, Jagged1, FGF receptor 1, and the transcription factor Sox2. Following specification, hair cells and supporting cells are defined within this region by a process that requires Math1, a bHLH transcription factor, and the additional Notch ligands, Jagged2 and Dll1. A final stage in the process of development of the organ of Corti again requires FGF signaling, this time through FGFR3, to direct a subset of the support cells to develop as pillar cells. While this model has received strong experimental support, there are still many unanswered questions. For example, FGF signaling is known to be critical for pillar cell development, but we have recently found that mutants in Fgfr3 also have an increase in outer hair cells. Our recent results further suggest that there may be an interaction between FGF signaling and another key regulator of hair cell development, the Notch pathway, but we know almost nothing about connections between these pathways. In our screens for other FGFs and other Notch pathway components that might play a role in cochlear development, we discovered that FGF20 is expressed in a highly specific pattern that coincides with the prosensory domain from E14 to E16 and that Hes related genes, Hesr1 and Hesr2, are expressed in this same domain, from E12.5. In this proposal we address these questions in three Specific Aims. Aim 1. Determine the role of FGF signaling and FGF20 in early cochlear development. Aim 2. Determine whether Hesr1 and Hesr2 are the downstream effectors of Jagged1/Notch. Aim 3. Determine whether Prox1 directly regulates expression of Fgfr3 in support cells of the developing organ of Corti? We will use a combination of molecular biological techniques, as well as analysis of transgenic and knockout mice, to accomplish these aims. Understanding the roles of the FGF and Notch pathways in cochlear development may lead to the design of treatments for congenital disorders. Moreover, a better understanding of the molecular pathways regulating normal development will be critical for rational strategies for hair cell replacement and regeneration in adult onset deafness.

描述（由申请人提供）：Corti器官的开发是一个严格调节的过程，其中，将耳蜗管的小“ POSSENSORY”结构域分类为各种类型的毛细胞和支持细胞。在过去的五年中，这一过程的模型主要是通过对发育表达基因突变的小鼠分析的。由p27表达定义的前期区域由Notch途径配体，JAGGED1，FGF受体1和转录因子SOX2指定。按照规范的规定，在该区域内定义了毛细胞和支持细胞，该过程需要MATH1，BHLH转录因子以及其他缺口配体Jagged2和DLL1。这次通过FGFR3再次需要FGF信号传导，以指导支持细胞的一部分以形成柱细胞。尽管该模型获得了强大的实验支持，但仍有许多未解决的问题。例如，已知FGF信号对于柱细胞的发育至关重要，但是我们最近发现FGFR3中的突变体的外毛细胞也增加。我们最近的结果进一步表明，FGF信号传导与毛细胞发育的另一个关键调节剂之间的相互作用，即Notch途径，但我们几乎对这些途径之间的连接一无所知。在我们的其他FGF和其他可能在人工耳蜗发育中起作用的Notch途径成分的屏幕中，我们发现FGF20以高度特异性的模式表达，与从E14到E16的Prosensory域重合，HES相关基因，HESR1和HESR2，HESR1和HESR2在E12.5中表达在同一域中。在此提案中，我们以三个具体目标解决了这些问题。目标1。确定FGF信号和FGF20在早期人工耳蜗发展中的作用。 AIM 2。确定HESR1和HESR2是否是JAGGED1/NOTCH的下游效应子。 AIM 3。确定Prox1是否直接调节Corti发育器官支持细胞中FGFR3的表达？我们将使用分子生物学技术以及转基因和基因敲除小鼠的分析来实现这些目标。了解FGF和Notch途径在人工耳蜗发展中的作用可能会导致先天性疾病的治疗方法。此外，对调节正常发育的分子途径的更好理解对于成人发作耳聋的毛细胞替代和再生的合理策略至关重要。