Role of endothelin signaling in the development of intermediate cells in the stria vascularis

摘要 血管纹是哺乳动物耳蜗的特化上皮结构，其产生内淋巴，富钾流体负责耳蜗腔的正耳蜗内电位。 这种正性细胞外电位是感觉细胞进行适当信号转导的主要驱动力， 耳朵，以及正常的听力。血管纹是听觉器官的“电池”。它位于 耳蜗的外侧壁，并由多层高度血管化的上皮组成。它是由 三种主要的细胞类型具有不同的胚胎起源：来自耳上皮的边缘细胞， 中间细胞，其是来源于迁移神经嵴细胞的特化黑素细胞样细胞，以及 来自耳间充质的基底细胞。中胚层衍生的血管散布在 这些细胞遍布整个纹。血管纹发育的缺陷是许多疾病的一部分， 人类遗传性耳聋综合征，包括先天性巨结肠和Waardenburg，Jervell和 Lange-Nielsen、Bartter和Sebastian综合征。在过去的十年里，我们做出了巨大的努力， 了解哺乳动物耳蜗感觉细胞的发育，目的是应用它们的 再生疗法的发展原则。相比之下，对发育过程的了解很少。 血管纹的潜力，甚至是由于衰老引起的视网膜退化的机制。我们的长期 目标是了解支配纹的发展的原则，并应用它们来设计 用于先天性耳聋或老年性耳聋病例的修复和再生治疗。神经嵴细胞是多能迁移胚胎细胞的瞬时群体。在内耳中，神经嵴细胞产生第VIII神经节的神经胶质和血管纹的中间细胞。中间细胞是正常听觉功能所必需的，尽管它们似乎与黑色素母细胞有着共同的起源，但黑色素本身并不是听觉所必需的。影响神经嵴发育或迁移的突变通常会导致包括耳聋在内的综合征。人内皮素受体B基因（Ednr B）突变导致先天性巨结肠。此综合征的感音神经性耳聋是血管纹萎缩缺乏中间细胞的结果。本研究的目的是探讨血管纹中神经嵴源性中间细胞的迁移、分化和与其他细胞的相互作用，以及内皮素信号在这些过程中的作用。

ABSTRACT The stria vascularis is a specialized epithelial structure of the mammalian cochlea that produces endolymph, the potassium-rich fluid responsible for the positive endocochlear potential of the cochlear lumen. This positive extracellular potential is the major driving force for proper signal transduction by sensory cells in the ear, and thus normal hearing. The stria vascularis is the “battery” of the auditory organ. It is localized in the lateral wall of the cochlea, and consists of a multilayered highly vascularized epithelium. It is composed of three main cell types with distinct embryonic origins: the marginal cells derived from the otic epithelium, the intermediate cells which are specialized melanocyte-like cells derived from migratory neural crest cells, and the basal cells that are derived from otic mesenchyme. Mesoderm-derived blood vessels are interspersed between these cells throughout the stria. Defects in the development of the stria vascularis are part of a number of inheritable deafness syndromes in humans, including Hirschsprung disease and Waardenburg, Jervell and Lange-Nielsen, Bartter and SeSAME syndromes. Over the past decade, a great effort has been made to understand the development of the sensory cells in the mammalian cochlea with the aim of applying their developmental principles to regenerative therapies. By contrast, very little is known about the developmental potential of the stria vascularis, or even the mechanisms of strial degeneration due to aging. Our long-term goal is to understand the principles that govern the development of the stria and apply them to devise reparative and regenerative therapies for cases of congenital strial defects or strial presbycusis. Neural crest cells are a transient population of multipotent migratory embryonic cells. In the inner ear, neural crest cells give rise to the glia of the VIIIth ganglion and the intermediate cells of the stria vascularis. Intermediate cells are necessary for normal strial function and although they seem to share a common origin with melanoblasts, melanin itself is not necessary for hearing. Mutations that affect neural crest development or migration often result in syndromes that include deafness. Mutations of the human endothelin receptor B gene (Ednrb) result in Hirschsprung's disease. The sensorineural deafness in this syndrome is a consequence of the atrophied stria vascularis that lacks intermediate cells. The goal of this proposal is to investigate the migration, differentiation and interactions of neural crest-derived intermediate cells with other cells in the stria vascularis and the role that Endothelin signaling plays in these processes.