Roles of hedgehog signaling in foregut development

刺猬信号在前肠发育中的作用

• 批准号: 8024397
• 负责人: JOHN A KLINGENSMITH
• 金额: $ 38.07万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8024397
• 关键词: Roles; hedgehog; signaling; foregut; development

DESCRIPTION (provided by Principal Investigator): Proper development of embryonic foregut derivatives is essential for mammalian survival at birth. The rostral endodermal foregut tube divides into ventral respiratory (larynx and trachea) and dorsal alimentary (esophagus and stomach) components. Remarkably little is known about the underlying mechanisms, despite their pragmatic importance. For example, defects in foregut compartmentalization result in common birth defects involving abnormal communications between these systems, known clinically as tracheoesophageal fistulas (TEF) and laryngo-esophageal clefts. Sonic hedgehog (Shh) is essential for generation of distinct laryngeal/tracheal and esophageal tubes, as the Shh-null mouse foregut is uncompartmentalized. Our preliminary data indicate that later Shh expression in the developing trachea and esophagus is critical for the stratification of foregut epithelia and development of specialized foregut mesoderm. Our overall hypothesis is that shh signaling acts as a master regulator of foregut development, initially to control tissue remodeling essential for formation of esophagus, trachea and larynx from a common precursor, and subsequently to pattern the endodermal and mesodermal tissues of these nascent organs. We propose a series of tissue-specific and temporal genetic manipulations of Shh expression and reception in the mouse embryo, coupled with histological and molecular analyses, to investigate the roles of Shh signaling in foregut development. Aim 1 determines the role of Shh signaling in normal separation of trachea from esophagus, the morphogenic process by which this occurs, and how the disruption of Shh signaling results in TEF. Aim 2 in turn addresses the separation of larynx from esophagus, with special attention to the role of neural crest-derived laryngeal cartilages in this process. Aim 3 elucidates the role of Shh in the different patterns of stratification and differentiation within the endoderm. In Aim 4, we determine the spatiotemporal functions of Shh signaling in differentiation of specialized foregut mesoderm, including the tracheal cartilage rings, trachealis smooth muscle, and esophageal smooth muscle. Altogether, these studies will provide important insight into the roles of Shh signaling in normal development and congenital defects of the trachea, esophagus, and larynx. PUBLIC HEALTH RELEVANCE: Proper development of embryonic foregut derivatives is essential for mammalian survival at birth. The rostral endodermal foregut tube divides into ventral respiratory (larynx and trachea) and dorsal alimentary (esophagus and stomach) components. These must then develop into functional organs. Little is known about the underlying mechanisms, despite their pragmatic importance. This proposal is for a research project to dissect the roles of the Sonic hedgehog intercellular signaling pathway in mouse foregut development. We elucidate critical roles in the initial compartmentalization of the common foregut tube, and in the organ-specific differentiation of endoderm and mesoderm. Our results are of direct relevance to the mechanisms of human foregut birth defects and potentially to the pathogenesis of esophageal cancer.

描述（由首席研究者提供）：适当开发胚胎衍生物对于出生时哺乳动物生存至关重要。内胚层的前肢管分为腹侧呼吸道（喉和气管）和背侧消化（食道和胃）成分。尽管具有务实的重要性，但对基本机制的了解知之甚少。例如，前述隔室化的缺陷导致涉及这些系统之间异常通信的常见出生缺陷，该系统在临床上被称为气管食管瘘（TEF）和larygo- phist虫 - 食管裂裂。 Sonic刺猬（SHH）对于生成不同的喉/气管和食管试管至关重要，因为SHH-NULL小鼠的前肢未被分节截图。我们的初步数据表明，后来在发育中的气管和食道中的SHH表达对于前肠上皮的分层和专门的前胚层的发展至关重要。我们的总体假设是，SHH信号传导起到了前身发育的主要调节剂，最初是从共同的前体中控制食管，气管和乳液至关重要的组织重塑，然后随后对这些Nascent Organs的内胚层和中胚层组织进行模型。我们提出了一系列的组织特异性和时间遗传操纵小鼠胚胎中的SHH表达和接收，并与组织学和分子分析相结合，以研究SHH信号在前肢发展中的作用。 AIM 1确定SHH信号在与食道的正常分离中的作用，发生这种情况的形态发生过程以及SHH信号的破坏如何导致TEF。 AIM 2反过来介绍了喉与食道的分离，并特别注意了神经衍生的喉软骨在此过程中的作用。 AIM 3阐明了SHH在内胚层内不同分层和分化模式中的作用。在AIM 4中，我们确定了SHH信号传导的时空函数在分化的专业中胚层中，包括气管软骨环，气管平滑肌和食管平滑肌。总的来说，这些研究将为SHH信号在正常发育中的作用和气管，食管和喉部的先天性缺陷提供重要见解。 公共卫生相关性：适当开发胚胎衍生物对于出生时的哺乳动物生存至关重要。内胚层的前肢管分为腹侧呼吸道（喉和气管）和背侧消化（食道和胃）成分。然后这些必须发展成功能器官。尽管具有务实的重要性，但对基本机制知之甚少。该建议是针对一个研究项目，旨在剖析小鼠发育中的声波刺猬间信号通路的作用。我们阐明了在公共试管的初始隔室以及内胚层和中胚层的器官特异性分化中的关键作用。我们的结果与人类前肢出生缺陷的机制直接相关，并可能与食管癌的发病机理有关。