Genetic Regulation of Inner Ear Formation

内耳形成的遗传调控

• 批准号: 8471094
• 负责人: Monte Westerfield
• 金额: $ 35.71万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8471094
• 关键词: Cells; Cephalic; Conductive hearing loss; Development; Dorsal; Ear; Ectoderm; Equilibrium; Funding; Gastrula; Gene Expression; Genes; Genetic; Goals; Health; Human; Labyrinth; Lateral; Lead; Learning; Mediating; Modeling; Molecular; Mutation; Otic Placodes; Pathway interactions; Pattern; Primordium; Regulation; Sensorineural Hearing Loss; Signal Pathway; Signal Transduction; Testing; To specify; Vesicle; Vestibular Aqueduct; Work; base; blastocyst; campomelic dysplasia; gastrulation; hindbrain; neural plate; receptor expression; research study; response; transcription factor

DESCRIPTION (provided by applicant): The long-term goal of the proposed studies is to understand how cells are specified to form the inner ear. The inner ear arises from a specialized set of cells, the otic placode that forms at the lateral edge of the neural plate adjacent to the hindbrain. The otic placode, like other cranial placodes, is thought to arise from a common precursor pool called the preplacodal ectoderm. Fgf signals from the early mesendoderm and later from the hindbrain are required to specify the otic placode, however it is currently unknown how cells are allocated to the preplacodal ectoderm or how they respond to the inductive signals that trigger their differentiation into the ear. Previous studies showed that Bmp signaling, in addition to Fgf signaling, is required for specification of the otic placode and that the Fgf and Bmp signaling pathways converge on a set of transcription factors, notably Dlx3b, Sox9a, and Foxi1, that mediate induction and differentiation of the otic primordium. Mutations or haploinsufficiency of FOXI1 or SOX9 in humans can lead to abnormal inner ear development and conductive hearing loss. The proposed study will test the hypothesis that these factors function as a molecular switch that triggers otic induction, changing the sensitivity of preotic cells from low to high Fgf sensitivity, and that this switch is regulated by a balance between Bmp and Fgf signals. The proposed studies will provide the first comprehensive explanation of the mechanisms underlying otic induction. 1. The proposed studies will test whether Bmp and Foxi1 form a positive regulatory loop to maintain Dlx3b expression in cells that form the preplacodal ectoderm. They will examine whether altering Bmp signaling or Foxi1 activity alters Dlx3b expression and subsequent preplacodal ectoderm formation. These experiments will elucidate the mechanism that underlies initial patterning of the preplacodal ectoderm. 2. The proposed studies will test whether Foxi1 directs cells to form the preplacodal ectoderm by differentially regulating their responses to Bmp and Fgf signaling. They will examine whether altering Foxi1 activity alters Fgf and/or Bmp receptor expression and downstream pathways. These experiments will explain how the balance between Fgf and Bmp signals is sensed and maintained. 3. The proposed studies will test whether Sox9a and Foxi1 function as a molecular switch that triggers otic induction by altering the activities of Foxi1 and Sox9a and examining the resulting effects on Fgf sensitivity and otic specification as indicated by marker expression and placode and vesicle formation. These experiments will elucidate the central mechanism of otic induction. The proposed studies of foxi1 and sox9a have direct relevance to human health. Enlarged vestibular aqueduct (EVA), the most common form of inner ear abnormality in humans, can be caused by digenic inheritance of a heterozygous mutation in the SLC26A4 gene and a heterozygous mutation in the FOXI1 gene. EVA is associated with fluctuating and sometimes progressive sensorineural hearing loss and disequilibrium. Haploinsufficiency in SOX9 leads to campomelic dysplasia with complications that include conductive hearing loss.

描述（由申请人提供）：拟议研究的长期目标是了解细胞如何被指定形成内耳。内耳起源于一组专门的细胞，耳基板形成于邻近后脑的神经板的侧边缘。耳基板，像其他颅基板，被认为是从一个共同的前体池称为前基板外胚层。来自早期中内胚层和后来来自后脑的Fgf信号是指定耳基板所必需的，然而目前尚不清楚细胞如何分配到前基板外胚层，或者它们如何响应触发它们分化成耳的诱导信号。以前的研究表明，BMP信号，除了FGF信号，需要规范的耳基板和Fgf和BMP信号通路会聚在一组转录因子，特别是Dlx 3b，Sox 9a，和Foxi 1，介导的诱导和分化的耳原基。人类FOXI 1或SOX 9的突变或单倍不足可导致内耳发育异常和传导性听力损失。这项研究将检验这一假设，即这些因素作为一个分子开关，触发耳诱导，改变耳前细胞的敏感性从低到高的FGF敏感性，这种开关是由Bmp和FGF信号之间的平衡调节。拟议的研究将提供第一个全面的解释机制的基础上耳诱导。1.拟议的研究将测试Bmp和Foxi 1是否形成正调控环，以维持Dlx 3b在形成前基板外胚层的细胞中的表达。他们将研究改变Bmp信号或Foxi 1活性是否会改变Dlx 3b表达和随后的前基板外胚层形成。这些实验将阐明前基板外胚层的初始模式的基础机制。2.拟议的研究将测试Foxi 1是否通过差异调节细胞对Bmp和Fgf信号的反应来指导细胞形成前基板外胚层。他们将研究改变Foxi 1活性是否会改变Fgf和/或Bmp受体表达和下游途径。这些实验将解释Fgf和BMP信号之间的平衡是如何被感知和维持的。3.拟议的研究将测试Sox 9a和Foxi 1是否作为分子开关，通过改变Foxi 1和Sox 9a的活性触发耳诱导，并检查对Fgf敏感性和耳特异性的影响，如标记物表达和基板和囊泡形成所示。这些实验将阐明耳诱导的中枢机制。foxi 1和sox 9a的研究与人类健康有直接关系。前庭水管扩大（伊娃）是人类最常见的内耳异常形式，可由SLC 26 A4基因杂合突变和FOXI 1基因杂合突变的双基因遗传引起。伊娃与波动性和有时进行性感音神经性听力损失和不平衡有关。SOX 9的单倍不足会导致肢端发育不良，并发症包括传导性听力损失。