Mechanisms of endoderm specification along the A-P axis

描述（由申请人提供）：尽管内胚层来源的器官（包括肺、肝、胰腺和肠）的先天性缺陷普遍存在，但令人惊讶的是，对决定内胚层器官原基沿沿着前后（A-P）轴形成的机制知之甚少，这是本研究的长期目标。我们发表的和初步的研究表明，内胚层图案是高度保守的脊椎动物物种，我们假设，一个生长因子，FGF 4，在体内建立这些肠道管域中起着核心作用。FGF 4的表达模式和我们的初步数据表明，FGF 4通过促进后内胚层细胞的命运和抑制前内胚层细胞的命运来形成肠管。本提案旨在确定这种情况发生的机制。我们发现，FGF 4可以直接调节A-P内胚层细胞的命运，并且FGF 4改变了体内内胚层细胞沿着A-P轴的正常迁移路径，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FGF 4靶基因在很大程度上是未鉴定的。我们已经确定了一个内胚层特异性，FGF 4响应基因编码FGF结合蛋白1（FGFbp 1）。我们的研究已经确定，FGFbp 1是分泌的，与FGF 4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在内胚层和肠管模式形成期间充当内胚层特异性FGF 4激动剂。我们将研究FGF 4信号传导模式的分子机制，发育中的肠管沿着A-P轴，具有以下目的：目的1。确定FGF 4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FGF 4靶基因在内胚层模式中的作用。目标3：探讨FGFbp 1在肠管发育过程中的作用及机制。铺设说明：拟议的研究解决了一个重要的问题;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使胚胎干细胞成为内胚层的重要可移植衍生物，例如产生胰岛素的β细胞，以治疗1型糖尿病患者。

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.