Developmental origins of the inner ear sensory organs

描述(申请人提供)：内耳是一个高度不对称的感觉结构，有明确的前后轴(A-P)和背腹轴(D-V)。在胚胎发育过程中，这些轴是如何从简单的上皮细胞、耳道胎盘以及参与这种模式的基因产生的，几乎完全未知。内耳感觉器官(由机械感觉毛细胞组成)精确地定位在无感觉膜迷路中，并代表实际耳朵组织的一小部分。它们的位置和方向对平衡和听力的正常功能至关重要。在这种复杂结构的发展过程中出现的任何问题都会导致平衡或听力障碍。我们的长期目标是确定内耳模式所必需的分子信号通路。非洲爪蛙在生命染料、活体成像和基因功能分析方面的进展，以及胚胎操作的简便性，为我们提供了独特的机会来解决我们在活胚胎和蝌蚪中提出的特定目标(SA)和假设(HYP)。SA 1：确定正常构图需要内耳胎盘或耳囊的哪些区域。Hyp.背侧和/或腹侧信号是内耳正常的A-P模式所必需的。SA 2：Hedgehog(HH)信号在发育中的内耳模式中的作用。Hyp.在耳道胎盘形成后，HH信号对于内耳的A-P和腹侧模式都是必需的。经典的Wnt信号在发育中的内耳模式中的作用。Hyp.WNT信号在耳囊形成后，在内耳的A-P和D-V模式中发挥作用。总结：与鼻子等其他感官器官相比，发育中的内耳缺乏再生能力，这可能有助于解释为什么耳聋是更常见的出生缺陷之一。一个关键的问题不仅是哪些分子诱导毛细胞的形成(耳朵中将声音转换为大脑解释的电输入的特殊细胞)，而且对实际听力和平衡更重要的是需要在新形成的内耳中形成这些新的毛细胞并将其放置在准确的位置。这项建议将确定哪些分子是将这些毛细胞放置在正确位置所必需的，以便它们能够发挥听力和平衡功能。蛙类内耳与人类内耳非常相似，为研究内耳发育提供了一个很好的模型。

DESCRIPTION (provided by applicant): The inner ear is a highly asymmetrical sensory structure with clearly defined anterior-posterior (A-P) and dorsal-ventral (D-V) axes. How these axes arise during embryonic development from a simple epithelium, the otic placode, and the genes involved in this patterning are almost completely unknown. Inner ear sensory organs (consisting of mechanosensory hair cells) are precisely positioned within the nonsensory membranous labyrinth and represent a small percentage of actual ear tissue. Their position and orientation are vital for normal function in balance and hearing. Any problems during the development of this complex structure would result in balance or hearing deficits. Our long-term goal is to determine the molecular signaling pathways necessary for inner ear patterning. Advances in vital dyes, intravital imaging and gene function assays in the African clawed frog, Xenopus laevis, as well as the ease with which embryological manipulations can be done, combine to offer us the unique opportunity to address our proposed specific aims (SA) and hypotheses (HYP) in living embryos and tadpoles. SA 1: Determine which regions of the inner ear placode or otocyst are required for normal patterning. HYP. Dorsal and/or ventral signals are necessary for normal A-P patterning of the inner ear. SA 2: Role of Hedgehog (Hh) signaling in the patterning of the developing inner ear. HYP. Hh signaling, after otic placode formation, is required for both A-P and ventral patterning of the inner ear. SA 3: Role of canonical Wnt signaling in the patterning of the developing inner ear. HYP. Wnt signaling, after otocyst formation, plays a role in A-P as well as D-V patterning of the inner ear. Lay Summary: The lack of regenerative potential of the developing inner ear in contrast to other sensory organs, such as the nose, may help explain why deafness is one of the more common birth defects. A key question is not just which molecules induce the formation of hair cells (specialized cells in the ear that transduce sound to electrical inputs for the brain to interpret) but more important for actual hearing and balance is the need to form and place these new hair cells in precise positions in the newly formed inner ear. This proposal will identify which molecules are necessary for putting these hair cells in the right place so they can function in hearing and balance. The frog inner ear is very similar to ours so it provides a good model for studying inner ear development.