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: 7291864
• 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/7291864
• 关键词: Role; BMP; FGF; signaling; during

Limb development is ideal for the interactions of various signaling pathways because of the wealth of information describing the genetic pathways and signaling molecules that pattern the three axis of the limb. Previously we have shown an essential role for FGF signaling during limb development by examining mice lacking 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 2005)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.

肢体发育对于各种信号通路的相互作用是理想的，因为丰富的信息描述了遗传通路和形成肢体三个轴的信号分子。以前，我们通过检查缺乏FGF配体的小鼠，已经显示了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，导致FGF信号传导控制肢体大小的见解（Verheyden JM等2005）。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。通过同时失活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，从而导致FGF的下调，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。