Genes Involved in Ear Development

摘要 外周听觉系统的正常发育需要协调部署 信号分子在无数细胞中引导适当的转录反应 对耳朵有贡献的组织。成纤维细胞生长因子(FGFs)是 耳朵正常发育所需的重要信号和成纤维细胞生长因子信号的减少 在几种人类综合征中导致感音神经性和/或传导性听力损失。完毕 激活成纤维细胞生长因子信号也是有害的。我们发现老鼠的遗失 DUSP6/MKP3，一种ERK磷酸酶，起到负反馈调节作用 成纤维细胞生长因子信号，并在形成耳朵所有三个分区的谱系中表达， 导致穿透性和表达不一的小体积、颅缝融合和传导性 听力损失。这些表型与由激活基因突变引起的表型相似 人类FGFRs 1-3，但在小鼠模型中未从听觉角度进行探索。 为了解决不适当激活成纤维细胞生长因子信号的总体假设 对耳朵的发育有不利影响，我们将使用小鼠的遗传学、基因和蛋白质 定位研究、测听和骨骼分析以确定耳廓和其他 携带FGFR功能增益和Dusp6零等位基因组合的小鼠的表型 并确定了其他ERK磷酸酶在耳廓中的独特和多余的作用 发展。我们的发现将有助于将注意力集中在不同的 成纤维细胞生长因子信号的激活物和抑制物目前可能不被认为是原因或 针对各种人类听力损失综合征的改良和药物治疗 靶向调控成纤维细胞生长因子信号，改善FGFR介导的其他途径 疾病可能在预防听力损失方面有更多的临床应用。最后，一个 对调节成纤维细胞生长因子信号转导的后果的详细理解可能需要 制定内耳修复或再生策略的重要参数 单元类型。叙述性 听力损失是人类最常见的感官缺陷，可由基因突变引起 成纤维细胞生长因子在发育过程中的信号水平。我们正在用小鼠来模拟基因 不适当激活成纤维细胞生长因子信号以了解听力损失的发展 这些条件。这些研究有望提供将用于开发疗法的知识。 因为听力损失。

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.