Roles of hedgehog signaling in foregut development

描述（由首席研究员提供）：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。鼻侧内胚层前肠管分为腹侧呼吸部分（喉和气管）和背侧消化部分（食道和胃）。尽管其实际意义重大，但人们对其潜在机制知之甚少。例如，前肠区隔的缺陷导致这些系统之间异常通信的常见出生缺陷，临床上称为气管食管瘘（TEF）和喉-食管裂。Sonic hedgehog基因（Shh）对于产生不同的喉/气管和食管管至关重要，因为Shh缺失的小鼠前肠是未区隔的。我们的初步数据表明，发育中的气管和食道后期Shh的表达对于前肠上皮的分层和特化前肠中胚层的发育至关重要。我们的总体假设是，shh信号作为前肠发育的主要调节器，最初控制组织重塑，这对从共同前体形成食管、气管和喉部至关重要，随后对这些新生器官的内胚层和中胚层组织形成模式。我们在小鼠胚胎中对Shh的表达和接受进行了一系列组织特异性和时间性的遗传操作，并结合组织学和分子分析，以研究Shh信号在前肠发育中的作用。目的1确定Shh信号在气管与食道正常分离中的作用，其发生的形态形成过程，以及Shh信号的破坏如何导致TEF。目的2反过来讨论喉与食道的分离，特别注意神经嵴衍生的喉软骨在这一过程中的作用。目的3阐明Shh在内胚层内不同的分层和分化模式中的作用。在Aim 4中，我们确定了Shh信号在特化前肠中胚层（包括气管软骨环、气管平滑肌和食管平滑肌）分化中的时空功能。总之，这些研究将为Shh信号在气管、食道和喉部的正常发育和先天性缺陷中的作用提供重要的见解。

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.