Role of BMP and FGF signaling during limb development

BMP 和 FGF 信号在肢体发育过程中的作用

• 批准号: 7338641
• 负责人: MARK B LEWANDOSKI
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7338641
• 关键词: Role; BMP; FGF; signaling; during

Like all three-dimensional objects, the limb consists of three axes. The long-term goal of this work is to understand the interactions of various signaling and genetic pathways that pattern these three axes of the developing limb of the mouse embryo. This will not only tell us how a limb forms in utero, but will tell us how certain signaling/genetic pathways interact with each other in other normal contexts in the developing embryo as well as in abnormal contexts such as cancer and congenital disease. The developing limb is ideal for such studies because a wealth of genetic and experimental embryological data provides a rich context in which to place new data. Previously we have shown an essential role for fibroblast growth factor FGF signaling during limb development by examining mice lacking genes that encode FGF ligands (Lewandoski et al. 2000 Nature Genetics 28:167, Sun et al 2000 Nature Genetics 25: 6 ). However, the complexity caused by Fgf gene redundancy has led us to consider approaching the problem by examining FGF receptor mutants leading to the insight that FGF signaling controls limb size (Verheyden JM et al 2005Development 132:4235). We are also studying the inter-relationship between FGF and BMP signaling. Current models of limb development suggest that BMP signaling plays a role in controlling the normal cell death that occurs in mesenchymal interdigit cells, sculpting the final digit pattern, but the exact role of BMPs in this process are unknown. By simultaneously inactivating the Bmp receptor gene, Bmpr1a as well as Fgf8 and Fgf4 specifically in the limb bud ectoderm, we have produced genetic evidence for a novel model in which the surface ectoderm must receive a BMP signal, resulting in down regulation of Fgfs which in turn induces apoptosis of the underlying mesenchyme. Thus both BMPs and FGF cooperate to control the essential cell function of programmed cell death. We are extending these studies by studying the role of BMP and FGF signaling in various aspects of limb development using mouse lines that express Cre in specific region of the developing limb. For example the only way to test the hypothesis that BMPs act as direct effectors of cell death is to inactivate BMPs receptors only in the lineage that undergoes cells death, without affect genes in nearby cells. We have achieved this using new Cre lines which allow Cre-mediated gene inactivation in these lineages. With these lines are asking: are BMPs are direct effectors of normal programmed cell death? If not, how is programmed cell death controlled? If so, how do BMPs achieve this endpont?

与所有三维对象一样，肢体由三个轴组成。这项工作的长期目标是了解各种信号和遗传途径的相互作用，这些信号和遗传途径对小鼠胚胎发育肢体的这三个轴形成模式。这不仅可以告诉我们肢体在子宫内是如何形成的，还可以告诉我们某些信号传导/遗传途径在发育中的胚胎的其他正常环境中以及在癌症和先天性疾病等异常环境中是如何相互作用的。发育中的肢体是此类研究的理想对象，因为丰富的遗传和实验胚胎学数据为放置新数据提供了丰富的背景。以前，我们通过检查缺乏编码FGF配体的基因的小鼠，已经显示了成纤维细胞生长因子FGF信号传导在肢体发育期间的重要作用（Lewandoski等2000 Nature Genetics 28：167，Sun等2000 Nature Genetics 25：6）。然而，Fgf基因冗余引起的复杂性使我们考虑通过检查FGF受体突变体来解决该问题，从而了解FGF信号传导控制肢体大小（Verheyden JM等2005Development 132：4235）。我们还在研究FGF和BMP信号传导之间的相互关系。目前的肢体发育模型表明，BMP信号在控制间充质趾间细胞中发生的正常细胞死亡中起作用，塑造最终的数字模式，但BMP在这一过程中的确切作用尚不清楚。通过同时灭活BMP受体基因，Bmpr1a以及Fgf8和Fgf4，特别是在肢芽外胚层，我们已经产生了一种新的模型，其中表面外胚层必须接收BMP信号，导致下调Fgfs，这反过来又诱导细胞凋亡的基础间充质的遗传证据。因此，BMP和FGF两者协同控制程序性细胞死亡的基本细胞功能。我们正在通过研究BMP和FGF信号在肢体发育的各个方面的作用来扩展这些研究，使用在发育肢体的特定区域表达Cre的小鼠品系。例如，检验BMP作为细胞死亡的直接效应物的假设的唯一方法是仅在经历细胞死亡的谱系中使BMP受体活化，而不影响附近细胞中的基因。我们已经实现了这一点，使用新的Cre线，使Cre介导的基因失活，在这些谱系。有了这些线是问：骨形成蛋白是正常的程序性细胞死亡的直接效应？如果不是，那么程序性细胞死亡是如何控制的呢？如果是这样，BMP如何实现这一目标？