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传导途径的相互作用来说是理想的，因为描述肢体三轴模式的遗传途径和信号分子的信息非常丰富。之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过程中的重要作用(Lewandoski等人2000 Nature Genetics 28:167，Sun等人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 受体突变体来解决这个问题，从而认识到 FGF 信号传导控制肢体大小（Verheyden JM 等人 2005）我们也在研究 FGF 和 FGF 之间的相互关系BMP 信号传导。目前的肢体发育模型表明，BMP 信号传导在控制间充质指间细胞中发生的正常细胞死亡、塑造最终的手指模式方面发挥着重要作用，但 BMP 在此过程中的确切作用尚不清楚。通过同时灭活肢芽外胚层中的 Bmp 受体基因 Bmpr1a 以及 Fgf8 和 Fgf4，我们为一种新模型提供了遗传证据，在该模型中，表面外胚层必须接收 BMP 信号，从而导致 FGF 下调，从而转诱导潜在间充质细胞凋亡。因此，BMP 和 FGF 共同控制程序性细胞死亡的基本细胞功能。我们正在扩展这些研究，使用在发育肢体特定区域表达 Cre 的小鼠系来研究 BMP 和 FGF 信号在肢体发育各个方面的作用。