Mechanisms of endoderm specification along the A-P axis.

内胚层沿 A-P 轴规范的机制。

• 批准号: 7092306
• 负责人: James M Wells
• 金额: $ 27.54万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7092306
• 关键词: Xenopus; apoptosis; biochemical evolution; biological signal transduction; cell biology; cell differentiation; cell growth regulation; cell migration; cell proliferation; chick embryo; developmental genetics; embryogenesis; endoderm; extracellular matrix; fibroblast growth factor; functional /structural genomics; genetic regulation; laboratory mouse; mammalian embryology; nonmammalian vertebrate embryology; protein structure function

DESCRIPTION (provided by applicant): Despite the prevalence of congenital defects of endodermally derived organs including the lungs, liver, pancreas and intestines, surprisingly little is known about the mechanisms that determine where the primordia for endodermal organs will form along the anterior-posterior (A-P) axis, which is the long-term goal of this research. Our published and preliminary studies show that endoderm patterning is highly conserved across vertebrate species and we hypothesize that that one growth factor, FGF4, plays a central role in establishing these gut tube domains in vivo. The expression pattern of FGF4 and our preliminary data suggest FGF4 patterns the gut tube by promoting posterior and repressing anterior endoderm cell fate. This proposal aims to determine the mechanisms by which this occurs. We show that FGF4 can directly regulate A-P endoderm cell fate and that FGF4 alters the normal path of migration of endoderm cells along the A-P axis in vivo, suggesting that both act to pattern the developing gut tube. Moreover, the FGF4-target genes that regulate endoderm patterning and gut tube development are largely unidentified. We have identified one endoderm specific, FGF4-responsive gene that encodes FGF binding protein 1 (FGFbp1). Our studies have determined that FGFbp1 is secreted, binds to FGF4, prevents it from becoming tethered to the extracellular matrix (ECM) and enhances its activity. These data support our hypothesis that FGFbpl acts as an endoderm-specific FGF4 agonist during endoderm and gut tube patterning. We will investigate the molecular mechanisms by which FGF4-signaling patterns the developing gut tube along the A-P axis with the following aims: Aim 1. Determine the cell-biological mechanisms by which FGF4 establishes gut tube domains in vivo. Aim 2. Investigate the role of evolutionarily conserved FGF4-target genes in endoderm patterning. Aim 3. Investigate the function and mechanism of action of FGFbp1 during gut tube development. Lay Description: The proposed studies address an important question; how does one cell type, endoderm, give rise to cells of the lung, liver, pancreas, stomach, thyroid and intestine. Understanding normal development of these organs will allow us to diagnose congenital abnormalities. Additionally, this information should allow us to coax embryonic stem cells into becoming important transplantable derivatives of endoderm, such as insulin-producing beta cells to treat patients with Type 1 diabetes.

描述（由申请人提供）：尽管内胚层衍生器官（包括肺、肝脏、胰腺和肠）普遍存在先天性缺陷，但令人惊讶的是，人们对决定内胚层器官原基沿前后位置形成的机制知之甚少。 A-P）轴，这是本研究的长期目标。我们已发表的初步研究表明，内胚层模式在脊椎动物物种中高度保守，我们假设一种生长因子 FGF4 在体内建立这些肠管结构域中发挥着核心作用。 FGF4 的表达模式和我们的初步数据表明 FGF4 通过促进后内胚层细胞命运和抑制前内胚层细胞命运来形成肠管模式。该提案旨在确定发生这种情况的机制。我们发现FGF4可以直接调节A-P内胚层细胞的命运，并且FGF4改变体内内胚层细胞沿A-P轴迁移的正常路径，这表明两者都对发育中的肠管起作用。此外，调节内胚层模式和肠管发育的 FGF4 靶基因在很大程度上尚未确定。我们已经鉴定出一种内胚层特异性 FGF4 响应基因，该基因编码 FGF 结合蛋白 1 (FGFbp1)。我们的研究已确定 FGFbp1 被分泌，与 FGF4 结合，防止其与细胞外基质 (ECM) 结合并增强其活性。这些数据支持我们的假设，即 FGFbpl 在内胚层和肠管图案化过程中充当内胚层特异性 FGF4 激动剂。我们将研究 FGF4 信号传导沿 A-P 轴发育的肠管模式的分子机制，目标如下： 目标 1. 确定 FGF4 在体内建立肠管结构域的细胞生物学机制。目标 2. 研究进化上保守的 FGF4 靶基因在内胚层模式形成中的作用。目标 3. 研究 FGFbp1 在肠管发育过程中的功能和作用机制。外行描述：拟议的研究解决了一个重要问题；一种细胞类型（内胚层）如何产生肺、肝、胰腺、胃、甲状腺和肠的细胞。了解这些器官的正常发育将使我们能够诊断先天性异常。此外，这些信息应该使我们能够诱导胚胎干细胞成为重要的可移植内胚层衍生物，例如用于治疗 1 型糖尿病患者的产生胰岛素的 β 细胞。