FGF in Sensory System Development

描述（由申请人提供）：Corti器官的发育是一个严格调控的过程，其中耳蜗管的小“前感觉”域被分选为各种类型的毛细胞和支持细胞。在过去的五年里，这一过程的模型已经出现，主要是通过分析发育表达基因突变的小鼠。由p27表达定义的前感觉区由Notch途径配体、Jagged 1、FGF受体1和转录因子Sox 2指定。以下规格，毛细胞和支持细胞在该区域内定义的过程中，需要数学1，bHLH转录因子，和额外的Notch配体，锯齿2和Dll 1。Corti器官发育过程的最后阶段再次需要FGF信号传导，这次是通过FGFR 3，以指导支持细胞的子集发育为支柱细胞。虽然这一模型得到了强有力的实验支持，但仍有许多问题没有得到解答。例如，已知FGF信号传导对柱细胞发育至关重要，但我们最近发现Fgfr 3的突变体也增加了外毛细胞。我们最近的研究结果进一步表明，FGF信号传导与毛细胞发育的另一个关键调节因子Notch通路之间可能存在相互作用，但我们对这些通路之间的联系几乎一无所知。在我们筛选可能在耳蜗发育中发挥作用的其他FGF和其他Notch通路组分时，我们发现FGF 20以高度特异性的模式表达，该模式与E14至E16的前感觉结构域相一致，并且Hes相关基因Hesr 1和Hesr 2在E12.5的相同结构域中表达。在本提案中，我们从三个具体目标来解决这些问题。目标1.确定FGF信号传导和FGF 20在早期耳蜗发育中的作用。目标2.确定Hesr 1和Hesr 2是否是Jagged 1/Notch的下游效应器。目标3：确定Prox 1是否直接调节Fgfr 3在发育中的Corti器官的支持细胞中的表达？我们将使用分子生物学技术的组合，以及转基因和基因敲除小鼠的分析，以实现这些目标。了解FGF和Notch通路在耳蜗发育中的作用可能会导致先天性疾病治疗方法的设计。此外，更好地了解调节正常发育的分子途径对于成人发病耳聋的毛细胞替代和再生的合理策略至关重要。

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.