Role of BMP and FGF signaling during limb development

在目前的工作中，我们正在研究BMP信号作为发生在间充质指间细胞的正常程序性细胞死亡的效应器的作用，从而在出生时没有蹼肢的动物中去除它们并雕刻最终的指骨模式。在之前的工作中，我们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，进而诱导底层间质的凋亡。因此，我们证明bmp通过调节FGF信号间接控制程序性细胞死亡。然而，需要强调的是，这一发现并不排除BMP信号在控制发育肢体细胞死亡中的直接作用。因此，我们扩展了这些研究，利用在肢体发育的特定区域表达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。例如，检验bmp作为细胞死亡的直接效应器这一假设的唯一方法是仅在经历细胞死亡的谱系中灭活bmp受体，而不影响附近细胞中FGF的表达。我们使用新的Cre系实现了这一点，这些Cre系允许Cre介导的基因失活。通过这些细胞系，我们已经确定bmp是细胞死亡的直接效应器（Dev Biol. 411: 266-76）。在一个偶然的发现中，我们发现去除肢体芽指间区BMP信号可以挽救对发育肢体手指区域BMP信号的需求。我们对这种拯救的努力可能会导致对肢体发育模式的基本理解。在另一项研究中，我们发现了FGFs和BMP之间一个重要的信号传导节点，这对肢体骨骼的正常发育至关重要。我们之前的工作表明，从肢体芽的远端结构分泌的特定FGFs调节肢体的正常生长和模式。在目前的工作中，我们正在产生遗传证据，表明骨形成蛋白的信号传递给骨骼元件的祖先群体，通过控制FGF拮抗剂的表达来调节FGF信号。这两种信号通路的联系不仅是对肢体如何形成模式的独特见解，而且可能为两种通路在其他发育环境或癌症期间如何相互作用提供模型。

In current work, we are studying the role of BMP signaling as effectors of normal programmed cell death that occurs in mesenchymal interdigit cells, thus removing them and sculpting the final digit pattern in animals that are born without webbed limbs. In previous work, we 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 we demonstrated that BMPs control programmed cell death indirectly, by regulating FGF signaling. However, it is important to emphasize that this insight does not exclude a direct role for BMP signaling in controlling cell death in the developing limb. Therefore, we extended 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 affecting FGF expression in nearby cells. We have achieved this using new Cre lines that allow Cre-mediated gene inactivation in these lineages. With these lines we have determined that BMPs are direct effectors of cell death (Dev Biol. 411: 266-76). In a serendipitous discovery, we have found that removal of a BMP signal to the limb bud interdigit zone rescues the requirement for a BMP signal to the digit region of the developing limb. Our efforts to understand this rescue may lead to a fundamental understanding of patterning in the developing limb. In another study, we have uncovered an important node of signaling between FGFs and BMP that is essential for normal development of the limb skeleton. Our previous work demonstrates that specific FGFs, secreted from a distal structure in the limb bud, regulate the normal outgrowth and patterning of the limb. In current work, we are generating genetic evidence that BMP signaling to the progenitor population of the skeletal elements regulates this FGF signal by controlling the expression of an FGF antagonist. This linking of the two signaling pathways is not only a unique insight into how the limb is patterned but may provide a model for how the two pathways interact in other developmental contexts or during cancer.