Developmental origins of the inner ear sensory organs

描述（由申请人提供）：内耳是一种高度不对称的感觉结构，具有明确的前后（A-P）和背腹（D-V）轴。在胚胎发育过程中，这些轴是如何从一个简单的上皮（耳基板）产生的，以及参与这种模式的基因几乎完全未知。内耳感觉器官（由机械感觉毛细胞组成）精确地定位在非感觉膜迷路内，并代表实际耳组织的一小部分。它们的位置和方向对于平衡和听力的正常功能至关重要。在这个复杂结构的发展过程中，任何问题都会导致平衡或听力缺陷。我们的长期目标是确定内耳模式所需的分子信号通路。在非洲爪蛙，非洲爪蟾，以及胚胎学操作可以做的容易，活体染料，活体成像和基因功能测定的进展，联合收割机，为我们提供了独特的机会，以解决我们提出的具体目标（SA）和假说（HYP）在活胚胎和蝌蚪。SA 1：确定内耳基板或耳囊的哪些区域需要正常的模式。HYP。背侧和/或腹侧信号对于内耳的正常A-P模式是必要的。SA 2：刺猬（Hh）信号在发育中的内耳模式中的作用。HYP。在耳基板形成后，Hh信号传导是内耳的A-P和腹侧模式所需的。SA 3：典型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模式中起作用。概述：与其他感觉器官（如鼻子）相比，发育中的内耳缺乏再生潜力，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仅是哪些分子诱导毛细胞的形成（耳朵中的专门细胞，将声音转换为大脑的电输入进行解释），但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并放置这些新的毛细胞。这项提案将确定哪些分子是将这些毛细胞放在正确位置所必需的，以便它们能够在听力和平衡方面发挥作用。青蛙的内耳与我们的非常相似，因此它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.