Roles of hedgehog signaling in foregut development

刺猬信号在前肠发育中的作用

• 批准号: 8515399
• 负责人: JOHN A KLINGENSMITH
• 金额: $ 30.1万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515399
• 关键词: Address; Affect; Attention; Birth; Breathing; Cartilage; Cells; Cellular biology; Cleaved cell; Communication; Congenital Abnormality; Coupled; Data; Defect; Development; Disease; Dorsal; Embryo; Embryonic Development; Endoderm; Epithelial; Epithelium; Erinaceidae; Esophageal; Esophagus; Generations; Genetic Markers; Human; Knockout Mice; Label; Laryngeal cartilage; Larynx; Lead; Life; Literature; Malignant neoplasm of esophagus; Mesenchymal; Mesoderm; Molecular; Molecular Analysis; Morphogenesis; Mus; Neural Crest; Newborn Infant; Operative Surgical Procedures; Organ; Paracrine Communication; Pathogenesis; Pattern; Population; Primitive foregut structure; Principal Investigator; Process; Research; Research Project Grants; Role; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Smooth Muscle; Specific qualifier value; Stomach; Stratification; System; Testing; Time; Tissues; Trachea; Tracheoesophageal Fistula; Transgenic Mice; Tube; Work; autocrine; base; cartilage development; feeding; genetic manipulation; insight; oral ectoderm; public health relevance; respiratory; smoothened signaling pathway; spatiotemporal; tool

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(由首席调查员提供)：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。吻部内胚层前肠管分为腹侧呼吸(喉和气管)和背侧消化(食道和胃)两部分。值得注意的是，人们对潜在的机制知之甚少，尽管它们具有重要的实用价值。例如，前肠分区的缺陷会导致常见的出生缺陷，涉及这些系统之间的异常通讯，临床上称为气管食管瘘(TEF)和喉-食管裂。Sonic Hedgehog(Shh)对于产生不同的喉/气管和食道管是必不可少的，因为Shh缺失的小鼠的前肠是未分割的。我们的初步数据表明，Shh在发育中的气管和食道中的表达对前肠上皮的复层和特化的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因子，最初控制共同前体形成食道、气管和喉所必需的组织重塑，随后形成这些新生器官的内胚层和中胚层组织。我们提出了一系列关于Shh在小鼠胚胎中表达和接收的组织特异性和时间性遗传操作，并结合组织学和分子分析，来研究Shh信号在前肠发育中的作用。目的1确定Shh信号在气管和食道正常分离中的作用，其发生的形态发生过程，以及Shh信号的中断如何导致TEF。目的2反过来解决喉与食道的分离，特别注意神经脊源性喉软骨在这一过程中的作用。目的3阐明Shh在内胚层不同层化和分化模式中的作用。在目标4中，我们确定了Shh信号在特化前肠中胚层分化中的时空功能，包括气管软骨环、气管平滑肌和食道平滑肌。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。 公共卫生相关性：胚胎前肠衍生物的适当开发对哺乳动物出生时的存活至关重要。吻部内胚层前肠管分为腹侧呼吸(喉和气管)和背侧消化(食道和胃)两部分。然后，这些器官必须发育成功能器官。人们对其潜在机制知之甚少，尽管它们具有重要的实用价值。这项建议是为了研究Sonic Hedgehog细胞间信号通路在小鼠前肠发育中的作用。我们阐明了在共同前肠管的初始区划中的关键作用，以及在内胚层和中胚层器官特异性分化中的关键作用。我们的结果与人类先天出生缺陷的机制直接相关，并可能与食道癌的发病机制有关。

项目成果

One shall become two: Separation of the esophagus and trachea from the common foregut tube.

• DOI: 10.1002/dvdy.24219
• 发表时间: 2015-03
• 期刊: Developmental dynamics : an official publication of the American Association of Anatomists
• 作者: Billmyre KK;Hutson M;Klingensmith J
• 通讯作者: Klingensmith J