Roles of hedgehog signaling in foregut development

描述（由主要研究者提供）：胚胎前肠衍生物的适当发育对哺乳动物出生时的存活至关重要。内胚层前肠管分为腹侧呼吸（喉和气管）和背侧消化（食管和胃）组成部分。值得注意的是，人们对潜在的机制知之甚少，尽管它们具有实用的重要性。例如，前肠区室化缺陷导致常见的出生缺陷，涉及这些系统之间的异常通信，临床上称为气管食管瘘（TEF）和喉食管裂。Sonic hedgehog（Shh）对于生成不同的喉/气管和食管管至关重要，因为Shh缺失小鼠前肠是未区室化的。我们的初步数据表明，以后Shh在气管和食管的发展是至关重要的前肠上皮细胞的分层和专门的前肠中胚层的发展。我们的总体假设是，shh信号作为一个主调节器的前肠发展，最初控制组织重塑形成食管，气管和喉从一个共同的前体必不可少的，并随后图案的内胚层和中胚层组织这些新生器官。我们提出了一系列的组织特异性和时间的遗传操作Shh的表达和接收在小鼠胚胎中，再加上组织学和分子分析，研究Shh信号在前肠发育中的作用。目的1确定Shh信号在气管与食管正常分离中的作用，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。目的2依次讨论喉与食管的分离，特别注意神经嵴衍生的喉软骨在此过程中的作用。目的3阐明Shh在内胚层分层和分化的不同模式中的作用。在目的4中，我们确定Shh信号传导在专门的前肠中胚层分化中的时空功能，包括气管软骨环、气管平滑肌和食管平滑肌。总而言之，这些研究将提供重要的洞察Shh信号在正常发育和先天性缺陷的气管，食管和喉的作用。 公共卫生相关性：胚胎前肠衍生物的适当发育对哺乳动物出生时的生存至关重要。内胚层前肠管分为腹侧呼吸（喉和气管）和背侧消化（食管和胃）组成部分。这些器官必须发育成功能器官。尽管其实际重要性，但对潜在的机制知之甚少。本计画是为一个研究计画，以剖析Sonic hedgehog细胞间讯息传递路径在小鼠前肠发育中所扮演的角色。我们阐明了共同的前肠管的初始区室化，并在器官特异性分化的内胚层和中胚层的关键作用。我们的研究结果与人类前肠出生缺陷的机制直接相关，并可能与食管癌的发病机制有关。

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.