Genes Involved in Ear Development

摘要 周围听觉系统的正常发育需要协调部署 信号分子来指导各种转录反应， 对耳朵有贡献的组织。成纤维细胞生长因子（FGF）是其中之一， 正常耳发育所需的重要信号和FGF信号的减少 在几种人类综合征中引起感音神经性和/或传导性听力损失。超过 FGF信号传导的激活也是有害的。我们发现老鼠的死亡 DUSP 6/MKP 3，一种ERK磷酸酶，作为负反馈调节剂， FGF信号传导，并且在引起耳的所有三个部分的谱系中表达， 导致颅外突出和表现性小，颅缝早闭和传导性 听力损失这些表型类似于由激活突变引起的表型， 人FGFRs 1-3，但在小鼠模型中从听觉角度尚未探索。 为了解决FGF信号传导的不适当激活 不利影响耳朵的发展，我们将使用小鼠遗传学，基因和蛋白质 定位研究，听力测定和骨骼分析，以确定耳和其他 携带Fgfr功能获得性和Dusp 6无效等位基因组合的小鼠的表型 并确定其他ERK磷酸酶在耳炎性疾病中的独特和冗余作用。 发展我们的发现将有助于将注意力集中在不同的可能性上， FGF信号传导的激活剂和抑制剂目前可能未被认为是致病的， 针对各种人类听力损失综合征进行改良， 目的是靶向调节FGF信号传导，以改善其他FGFR介导的 条件可能具有用于听力损失预防的额外临床应用。最后 对调节FGF信号传导的后果的详细理解可能是 在发展内耳修复或再生策略中的重要参数 细胞类型。叙事 听力损失是人类最常见的感觉缺陷，可能是由改变听觉系统的突变引起的。 成纤维细胞生长因子（FGF）信号在发展过程中的水平。我们用老鼠来模拟遗传 FGF信号不适当激活的病例，以了解听力损失的发展， 了以下条件这些研究有望为开发治疗方法提供知识 治疗听力损失

Abstract Normal development of the peripheral auditory system requires coordinated deployment of signaling molecules to direct appropriate transcriptional responses in the myriad tissues that contribute to the ear. Fibroblast growth factors (FGFs) are among the important signals required for normal ear development and reductions in FGF signaling cause sensorineural and/or conductive hearing loss in several human syndromes. Over activation of FGF signaling is also detrimental. We found that loss of mouse DUSP6/MKP3, an ERK phosphatase that functions as a negative feedback regulator of FGF signaling, and is expressed in lineages giving rise to all three divisions of the ear, causes variably penetrant and expressive small size, craniosynostosis and conductive hearing loss. These phenotypes are similar to those caused by activating mutations in human FGFRs 1-3, but are unexplored from an auditory perspective in mouse models. To address the overall hypothesis that inappropriate activation of FGF signaling adversely affects development of the ear, we will use mouse genetics, gene and protein localization studies, audiometrics and skeletal analyses to determine the otic and other phenotypes of mice bearing combinations of Fgfr gain-of-function and Dusp6 null alleles and determine the unique and redundant roles of other ERK phosphatases in otic development. Our findings will help to focus attention on the likelihood that different activators and inhibitors of FGF signaling may currently be unrecognized as causal or modifying for various human hearing loss syndromes and that pharmacologic treatments aimed at targeted modulation of FGF signaling for amelioration of other FGFR-mediated conditions may have additional clinical applications for hearing loss prevention. Finally, a detailed understanding of the consequences of modulating FGF signaling is likely to be an important parameter in developing strategies for repair or regeneration of inner ear cell types. Narrative Hearing loss is the most common human sensory deficit and can be caused by mutations that change the levels of Fibroblast Growth Factor (FGF) signaling during development. We are using mice to model genetic cases of inappropriate activation of FGF signaling in order to understand the development of hearing loss in these conditions. These studies are expected to contribute knowledge that will be used in developing therapies for hearing loss.