Role of Ectodermal Signals in Limb Bud Outgrowth and Development

外胚层信号在肢芽生长和发育中的作用

基本信息

批准号：
7894876
负责人：
TREVOR J WILLIAMS
金额：
$ 36.93万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7894876
关键词：
Abdomen Address Affect Alleles Animal Model Apical Ectodermal Ridge Appearance Child Clinic Complex Congenital Abnormality Data Defect Development Diagnosis Ectoderm Elements Embryo Embryonic Development Event Exhibits FGF10 gene FGF8 gene Face Family Feedback Felis catus Fibroblast Growth Factor Forelimb Future Genes Genetic Goals Growth Heart Hindlimb Human Infant Knockout Mice Knowledge Lateral Lead Light Limb Bud Limb Development Limb structure Mammals Mechanics Medicine Mesenchyme Modeling Molecular Molecular Genetics Morphogenesis Mus Natural regeneration Newborn Infant Organ Organogenesis Outcome Parents Pathology Pathway interactions Pattern Pharmacologic Substance Phase Phenotype Pregnancy loss Prevention Process Quality of life Reagent Regulation Role Secondary to Shapes Signal Pathway Signal Transduction Signaling Molecule Specific qualifier value Structure System Testing Time Tissues Up-Regulation Vertebrates Wnt proteins appendage computerized data processing dosage gain of function gene interaction insight limb regeneration loss of function malformation mouse Cre recombinase mutant organ regeneration prevent receptor skeletal spine bone structure

项目摘要

The development and patterning of an embryo requires coordinate interactions between different tissue layers at appropriate times for successful outcome. Mechanistically, this is driven by a group of conserved signaling molecules, their receptors, and their downstream transcriptional effectors. Disruptions of these molecules and their signaling processes can lead to birth defects and/or pregnancy loss. Although many birth defects have clear environmental and genetic causes, insufficient information exists concerning the mechanisms of development to enable the majority of these defects to be detected or prevented pre-natally. An important goal is to develop animal models of congenital malformations that will lead to mechanistic insight into the diagnosis and treatment of related human birth defects. The process of mammalian limb induction, outgrowth and patterning is a pertinent model that can be used to investigate multiple aspects of development and signaling. The development of the limb relies on reciprocal signaling between cells expressing factors belonging to the Fgf family of secreted molecules, especially Fgf8 and Fgf10. Further evidence has implicated another signaling pathway, involving Wnt proteins and -catenin, in two crucial events during limb development. First, the canonical Wnt signaling pathway is needed for establishment of the initial domain of Fgf10 expression. Second, this pathway is required for formation of the apical ectodermal ridge (AER), which is a major organizing center for limb outgrowth and patterning. Recent evidence indicates that the upregulation of canonical Wnt signaling in the early mouse embryonic ectoderm via the stabilization of -catenin greatly upregulates Fgf8 expression. The consequences of these molecular changes are that limb formation is induced along the entire lateral axis between the forelimb and hindlimb buds. This leads to the appearance of a “unilimb” structure that generates a mechanical constraint on normal axis elongation in the mouse trunk. Two hypotheses were generated by these observations: (1) the up-regulation of Fgf8 is responsible for the majority the limb patterning defects observed in the -catenin gain of function experiment; (2) -catenin gain of function can dispense with the requirement of Fgf10 in limb induction. This application will directly test these two hypotheses using available mouse knockout and transgenic strains and will generate a new Fgf8 gain of function allele that can be used to extend these analyses in future. Ultimately the results of this study will provide new insight into limb induction and patterning as well as provide information into the underlying causes of related human birth defects.

胚胎的发育和模式化需要不同组织之间的协调相互作用从机制上讲，这是由一群保守的人驱动的。信号分子、其受体及其下游转录效应子。分子及其信号传导过程可能导致出生缺陷和/或流产。缺陷有明显的环境和遗传原因，但有关该缺陷的信息不充分使大多数缺陷能够在产前检测或预防的发育机制。一个重要的目标是开发先天性畸形的动物模型，从而获得机制上的见解进入相关人类出生缺陷的诊断和治疗。哺乳动物肢体的诱导、生长和形成的过程是一个相关的模型，可以用于研究肢体的发育和信号传导的多个方面。表达属于分泌分子 Fgf 家族的因子的细胞之间的相互信号传导，特别是 Fgf8 和 Fgf10，进一步的证据表明涉及 Wnt 蛋白的另一个信号通路。和 β-连环蛋白，在肢体发育过程中的两个关键事件中首先，典型的 Wnt 信号通路是。其次，该途径是建立 Fgf10 表达初始域所必需的。顶端外胚层脊（AER）的形成，它是肢体生长和发育的主要组织中心最近的证据表明早期小鼠中经典 Wnt 信号的上调。胚胎外胚层通过 -catenin 的稳定作用大大上调 Fgf8 的表达。这些分子变化中的一个是沿着前肢之间的整个横轴诱导肢体形成和后肢芽，这导致了产生机械的“单肢”结构的出现。对小鼠躯干法向轴伸长的限制由此产生了两个假设。观察结果：(1) Fgf8 的上调是观察到的大部分肢体模式缺陷的原因 -连环蛋白功能增益实验中； (2) -连环蛋白功能增益可免去要求； Fgf10 在肢体诱导中的应用将使用可用的小鼠敲除技术直接测试这两个假设。和转基因菌株，并将产生新的 Fgf8 功能获得等位基因，可用于扩展这些最终，这项研究的结果将为肢体感应和模式化提供新的见解。以及提供有关人类出生缺陷的根本原因的信息。