Molecular Basis For The Morphogenesis Of The Inner Ear

内耳形态发生的分子基础

• 批准号: 6674016
• 负责人: Doris Wu
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6674016
• 关键词: Retroviridae; bone morphogenetic proteins; cell differentiation; chick embryo; developmental genetics; developmental neurobiology; gene expression; gene targeting; genetic mapping; histogenesis; histopathology; laboratory mouse; labyrinth; otocyst /otolith; transfection /expression vector; transforming growth factors

Proper patterning of the inner ear requires instructive signaling from surrounding tissues including the hindbrain, mesoderm and notochord. The molecular mechanisms underlying these inductive events are largely unknown. One of our major accomplishments this year (in collaboration with Dr. Douglas Epstein at the University of Pennsylvania) was to demonstrate that Sonic Hedgehog (Shh) is an important signal in specifying the inner ear. The ventral portion of the neural tube (floor plate) and the notochord are thought to be the primary sources of SHH for the inner ear. In Shh knock out mice, ventral inner ear structures such as the saccule and cochlea fail to develop. Medial and lateral structures such as the endolymphatic duct and lateral canal, appear to be specified initially but fail to develop at later stages. The process of neuroblast delamination from the anterior region of the otocyst to form the cochleovestibular ganglion is also affected in the Shh mutants. Gene expression analyses of Shh knock out mutant mice as well as transgenic mice that ectopically express Shh in the otocyst show that several genes such as Ngn1, Pax2, Otx2, Tbx1, and Brn4 are likely downstream targets of SHH. Another long-standing interest in the laboratory is to investigate the role of Bone Morphogenetic Proteins (BMPs) in the developing inner ear. Various Bmps are expressed in the developing otic epithelium and regions of surrounding mesenchyme during different stages of development. Previously, we have shown that BMPs are important for the semicircular canal development as well as the formation of the otic capsule. During this year, by correlating the expression patterns of various BMPs with the localization of cells responding to them, we postulated that BMPs mediate epithelial to mesenchymal interactions in specific regions of the inner ear such as the endolymphatic duct and semicircular canals. Furthermore, the formation of sensory and non-sensory components of the inner ear are most likely coupled during development, even though the molecular mechanisms involved in this coordination are largely unknown. FGF-3 and 10 (Fibroblast growth factor) are expressed in the presumptive sensory organs while one of their receptors, FGFR2-IIIb, is primarily expressed in the non-sensory epithelium. These patterns suggest that FGFs in the sensory organ could play such a role in coordinating sensory and non-sensory development. Using a recombinant avian retrovirus encoding FGF-3 or beads soaked with FGF-2, we showed that FGFs promote canal development in the chicken inner ear. These effects of FGFs are mediated by induction of Bmp2 in the canal pouch region, thus identifying a molecular pathway whereby sensory tissue can induce non-sensory development.

内耳的适当图案需要来自周围组织，包括后脑，中胚层和脊索的启发性信号。这些电感事件的分子机制在很大程度上是未知的。我们今年的主要成就之一（与宾夕法尼亚大学的道格拉斯·爱泼斯坦博士合作）是证明Sonic Hedgehog（SHH）是指定内耳的重要信号。神经管的腹侧部分（地板板）和脊索被认为是内耳的SHH的主要来源。在SHH敲出小鼠中，腹侧内耳结构（如扫视和耳蜗）无法发展。内侧和外侧结构（例如内淋巴管和侧管）似乎是最初指定的，但在后期未能开发。在SHH突变体中，神经囊肿的神经细胞分层的过程也受到了头孢菌神经节的形成。 SHH的基因表达分析敲除突变小鼠以及在耳囊中异位表达SHH的转基因小鼠表明，诸如NGN1，PAX2，OTX2，TBX1和BRN4之类的几个基因可能是SHH的下游靶标。 对实验室的另一个长期兴趣是研究骨形态发生蛋白（BMP）在发育中的内耳中的作用。在发育的不同阶段，在发育中的耳朵上皮和周围间质区域中表达了各种BMP。以前，我们已经表明，BMP对于半圆形管的发育以及耳囊的形成很重要。在今年，通过将各种BMP的表达模式与响应它们的细胞的定位相关联，我们假设BMP介导了内耳特定区域的间充质相互作用（例如内淋巴管和半圆管）的间质相互作用。 此外，即使这种协调所涉及的分子机制在很大程度上未知，内耳的感觉和非感官成分的形成很可能是在发育过程中耦合的。 FGF-3和10（成纤维细胞生长因子）在推定的感觉器官中表达，而其受体之一FGFR2-IIIB主要在非感官上皮中表达。这些模式表明，感觉器官中的FGF可以在协调感觉和非感官发展中发挥这种作用。使用编码FGF-3或用FGF-2浸泡的珠子的重组禽逆转录病毒，我们表明FGFS促进了鸡内耳的运河发育。 FGF的这些作用是通过在运河袋区域诱导BMP2介导的，从而鉴定出一种分子途径，从而使感觉组织可以诱导非感官发育。