Role of BMP and FGF signaling during limb development

肢体发育是各种信号通路相互作用的理想选择，因为丰富的信息描述了肢体三轴的遗传通路和信号分子。之前，我们通过检测缺乏FGF配体的小鼠，证明了FGF信号在肢体发育过程中的重要作用（Lewandoski et al. 2000 Nature Genetics 28:7 7; Sun et al. 2000 Nature Genetics 25:6）。然而，Fgf基因冗余导致的复杂性使我们考虑通过检查Fgf受体突变来解决问题，从而了解到Fgf信号控制肢体大小（Verheyden JM et al 2005）。我们也在研究Fgf和BMP信号之间的相互关系。目前的肢体发育模型表明，BMP信号在控制发生在间充质指间细胞的正常细胞死亡中起作用，塑造最终的指模式，但BMP在这一过程中的确切作用尚不清楚。通过同时灭活肢体芽外胚层中Bmp受体基因Bmpr1a以及Fgf8和Fgf4，我们已经为一种新的模型提供了遗传证据，在这种模型中，表面外胚层必须接收Bmp信号，导致FGFs的下调，进而诱导下层间质凋亡。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，利用在发育肢体的特定区域表达Cre的小鼠品系，研究BMP和FGF信号在肢体发育的各个方面的作用。

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.