Signals Integrating Cellular Dynamics to Sculpt the Inner Ear (A1)

信号整合细胞动力学来塑造内耳 (A1)

• 批准号: 8824915
• 负责人: Suzanne L Mansour
• 金额: $ 45.56万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824915
• 关键词: Ablation; Animal Model; Auditory; Automobile Driving; Behavior; Cell Proliferation; Cell Shape; Cells; Characteristics; Chemicals; Chick Embryo; Data; Development; Diagnosis; Embryo; Epithelial; Epithelium; Event; Experimental Models; FGF10 gene; FGF3 gene; Fibroblast Growth Factor; Foundations; Gene Expression; Genetic; Growth Factor; Hearing problem; Human; Knowledge; Labyrinth; Lateral; Molecular Genetics; Morphogenesis; Mus; Mutation; Organ; Pathway interactions; Pattern; Primordium; Process; Publishing; Research Personnel; Role; SHH gene; Sensory; Shapes; Signal Pathway; Signal Transduction; Squamous Cell; System; Techniques; Testing; Time; Work; cell behavior; cell fate specification; dosage; equilibration disorder; gain of function; hearing impairment; human subject; inhibitor/antagonist; membranous labyrinth; molecular marker; novel; novel strategies; otoconia; prevent; research study; time use

DESCRIPTION (provided by applicant): Misregulation of intercellular signaling disrupts inner ear morphogenesis in human subjects and animal models, leading to hearing and balance disorders. Normal morphogenesis of the inner ear's membranous labyrinth requires temporal integration of regional and cell fate specification with changes in cell behavior. Past work has begun to identify changes in otocyst gene expression downstream of signals, including BMP, FGF and SHH, but much less is known about the cell behaviors driving morphogenesis and how these behaviors are coordinated temporally with progressive restriction of cell fates to generate the mature vestibular and cochlear compartments. Using temporally and spatially controlled loss- and gain-of-function in chick and mouse embryos, we propose to test the general hypothesis that BMP/TGFss, FGF and HH signaling are integrated to regulate otocyst regional and cell fate specification and cell behavior to initiate normal morphogenesis of the vestibular and cochlear compartments of the developing membranous labyrinth. Our preliminary data provide proof-of-principle for our approach. In control chick embryos, we identified a columnar-to-squamous cell shape change in the dorsolateral otocyst epithelium that occurs concomitant with thinning and expansion to form the primordial canal pouch. Spatiotemporally controlled loss- and gain-of-function experiments showed that BMP/SMAD signaling is both necessary and sufficient for this cell shape change. In addition, similar chick misexpression experiments revealed a common intersection point regulating BMP/SHH signaling during early otocyst dorsoventral patterning and morphogenesis. In mouse, we found that otocyst-derived FGF3 and FGF10 signals, in addition to their well-known roles in vestibular morphogenesis, are required to initiate cochlear morphogenesis. However, these epithelial signals are not required for early otocyst regional patterning, which is normal in FGF-deficient otocysts. Therefore, we propose to test the specific hypotheses that 1) temporal integration of BMP/TGFss, FGF and HH signaling controls three key early steps of otocyst morphogenesis: primordial canal outgrowth, subdivision of the primordium into vertical and lateral canal pouches and initial cochlear outgrowth, and 2) that such signaling coordinates otocyst regional and/or cell fate specification with changes in relevant cell behaviors. Our proposal takes advantage of the unique expertise of a team of established investigators using state-of-the-art molecular genetic and embryologic techniques in two animal models with complementary strengths that will illuminate important differences and similarities in mechanisms driving key morphogenetic steps downstream of growth factor signaling. This will advance the field by providing a novel understanding of how signaling pathways are integrated to control initiation of vestibular and cochlear morphogenesis, and how these signals coordinate specification of cell fate and changes in cell behavior to initiate and sculpt a normally functioning membranous labyrinth. Such information provides an essential foundation for understanding and ultimately preventing human hearing loss.

描述（由申请人提供）：细胞间信号传导的正调破坏了人类受试者和动物模型中的内耳形态发生，导致听力和平衡疾病。内耳膜迷宫的正常形态发生需要区域和细胞命运规范与细胞行为变化的时间整合。过去的工作已经开始确定信号下游的耳囊基因表达的变化，包括BMP，FGF和SHH，但对驱动形态发生的细胞行为以及这些行为如何在时间上与细胞命运进行逐步协调以产生成熟的前庭和同志隔室的逐渐限制。在雏鸡和小鼠胚胎中使用时间和空间控制的功能损失和功能获得，我们提出的一般假设是，BMP/TGFS，FGF和HH信号被整合在一起以调节耳状和细胞命运的规范和细胞行为，以启动对前提组的正常形态，并构成了成像的正常形成。我们的初步数据为我们的方法提供了原则证明。在对照雏鸡的胚胎中，我们确定了背外侧耳囊上皮的柱状细胞形状变化，该上皮与稀疏和膨胀形成原始管袋。空间控制的损失和功能获取实验表明，BMP/SMAD信号对于这种细胞形状的变化既需要且足够。此外，类似的小鸡Misexpression实验表明，在早期耳尾腹形成和形态发生过程中调节BMP/SHH信号的共同交点。在小鼠中，我们发现耳囊衍生的FGF3和FGF10信号除了它们在前庭形态发生中众所周知的作用外，还需要引发耳蜗形态发生。但是，这些上皮信号不需要早期的耳囊区域模式，这在FGF缺乏的耳囊中是正常的。 Therefore, we propose to test the specific hypotheses that 1) temporal integration of BMP/TGFss, FGF and HH signaling controls three key early steps of otocyst morphogenesis: primordial canal outgrowth, subdivision of the primordium into vertical and lateral canal pouches and initial cochlear outgrowth, and 2) that such signaling coordinates otocyst regional and/or cell命运规格随相关细胞行为的变化而变化。我们的建议利用了一个成立研究人员的独特专业知识，使用最先进的分子遗传学和胚胎学技术在具有互补强度的两个动物模型中使用了互补的强度，这将阐明重要的差异和相似之处，以驱动下游生长因子信号的关键形态学步骤。这将通过对信号通路如何整合到控制前庭和耳蜗形态发生的启动以及这些信号如何坐标细胞命运的规范以及细胞行为的变化以启动和雕刻正常功能正常的膜膜迷宫的情况来推动这一领域。这些信息为理解并最终防止人类听力损失提供了重要的基础。