Developmental origins of the inner ear sensory organs

描述（由申请人提供）：内耳是一个高度不对称的感觉结构，具有清晰的前后轴、背腹轴和内外侧轴。在胚胎发育过程中，这些轴是如何从一个简单的上皮细胞产生的，以及与这种模式有关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）精确地位于非感觉膜迷宫内，代表实际耳组织的一小部分。它们的位置和方向对平衡和听力的正常功能至关重要。在这个复杂的结构发育过程中，任何问题都会导致平衡或听力障碍。该基板经过大量的生长、形态发生、分化和选择性细胞死亡形成成体内耳。在非洲爪蟾（Xenopus laevis）的生命染料、活体成像和基因功能分析方面的进展，以及胚胎学操作的便便性，结合起来为我们提供了一个独特的机会，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）。问题1：描述导致镜像复制内耳的胚胎操作。沿前后轴行半消融，不需切除或多或少，以产生重复镜像。SA 2: Hedgehog （Hh）信号在内耳发育过程中的作用。Hh信号参与了前后模式。SA 3: Wnt信号在内耳发育模式中的作用。典型的Wnt信号通路参与背腹侧模式，而非典型的平面细胞极性（PCP）通路参与形态发生和毛细胞取向。发育中的内耳与嗅觉等其他基板相比，缺乏再生潜力，这可能有助于解释为什么耳聋是一种更常见的出生缺陷，而不是其他感觉基板衍生结构。一个关键的问题不仅仅是哪些分子会诱导毛细胞的形成，更重要的是，对于实际的听力和平衡来说，需要在新形成的内耳中形成和放置这些新毛细胞的精确位置。

DESCRIPTION (provided by applicant): The inner ear is a highly asymmetrical sensory structure with clearly defined anterior-posterior, dorsal- ventral, and medial-lateral 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. The placode undergoes a great deal of growth, morphogenesis, differentiation and selective cell death to form the adult inner ear. 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: Characterize an embryonic manipulation resulting in mirror image duplicated inner ears. Hyp. Half ablations along the anterior-posterior axis and not removal of greater or lesser amounts are necessary to generate mirror image duplications. SA 2: Role of Hedgehog (Hh) signaling in the patterning of the developing inner ear. Hyp. Hh signaling is involved in anterior-posterior patterning. SA 3: Role of Wnt signaling in the patterning of the developing inner ear. Hyp. Canonical Wnt signaling is involved in dorsal-ventral patterning while the noncanonical, Planar Cell Polarity (PCP), pathway is involved in morphogenesis and hair cell orientations. The lack of regenerative potential of the developing inner ear in contrast to other placodes, such as the olfactory, may help explain why deafness is one of the more common birth defects as opposed to those in other sensory placode derived structures. A key question is not just which molecules induce the formation of hair cells 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.