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中的正常程序性细胞死亡的效应器所起的作用，从而去除它们并在出生时没有鳍状肢体的动物中塑造最终的手指模式。以前的工作为一种新的模型提供了遗传学证据，在该模型中，表面外胚层必须接收BMP信号，导致FGFs下调，进而诱导底层间充质细胞凋亡。因此，我们证明BMPs通过调节成纤维细胞生长因子信号间接控制细胞程序性死亡。然而，必须强调的是，这一见解并不排除BMP信号在控制肢体发育中的细胞死亡方面的直接作用。因此，我们通过研究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，使用在发育肢体特定区域表达Cre的小鼠系。例如，检验BMPs作为细胞死亡直接效应因子的假设的唯一方法是，仅在经历细胞死亡的谱系中灭活BMPs受体，而不影响附近细胞中的FGF表达。我们已经使用新的Cre品系实现了这一点，这种品系允许Cre介导的基因在这些谱系中失活。这些问题是：BMP是正常的程序性细胞死亡的直接影响因素吗？如果不是，程序性细胞死亡是如何控制的？如果是这样，BMP是如何实现这一目标的？在一个偶然的发现中，我们发现，将BMP信号移至肢芽指间区，可以挽救对发育中肢体的指区的BMP信号的需求。我们努力理解这次救援可能会导致对发育中肢体的模式有一个基本的理解。在另一项研究中，我们发现了FGFs和BMP之间的一个重要信号节点，它对肢体骨骼的正常发育至关重要。我们之前的工作，如上所述，证明了特定的FGFs，从肢芽的远端结构中分泌出来，调节肢体的正常生长和模式。在目前的工作中，我们正在产生遗传学证据，表明BMP向骨骼元素的前体群体发出信号，通过控制成纤维细胞生长因子拮抗剂的表达来调节这种成纤维细胞生长因子信号。这两个信号通路的连接不仅是对肢体如何形成模式的独特洞察，而且可能为这两个通路在其他发育背景下或癌症期间如何相互作用提供一个模型。

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 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 are 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 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? 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, cited above, 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.