Role of BMP and FGF signaling during limb development

在以前的工作中，我们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，我们通过在肢体发育的特定区域表达Cre的小鼠品系来研究BMP和FGF信号在肢体发育的各个方面的作用，从而扩展了这些研究。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。通过这些线条，我们已经确定BMP是细胞死亡的直接效应因子(Dev Biol.411：266-76)。在目前的工作中，我们证明了MEIS同源结构域转录因子沿小鼠肢芽近端(PD)轴的梯度与远端成纤维细胞生长因子信号的抑制作用反平行并由其形成。消除MEI会导致肢体过早远端和近端的PD节段边界，并导致青光眼。我们的结果表明，MEIS转录因子解释成纤维细胞生长因子信号，沿着肢芽PD轴传递位置信息。这些发现为脊椎动物肢体中PD身份的产生建立了一个新的模型，并为解释轴向模式过程中成纤维细胞生长因子信号梯度提供了分子基础(Sci Adv，2020年，PMID：32537491)。在正在进行的工作中，我们正在确定远端成纤维细胞生长因子信号在后肢骨盆形态和分化中的作用。我们先前已经证明这些成纤维细胞生长因子信号位于骨形态发生蛋白受体1a的下游(发展，2007年，PMID：17537800)。我们现在正在使用复杂的遗传学和尖端的基因表达图像来定义哪些FGFs负责形成这种最近端的元件并启动肢体形成。

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 current work, we showed that a gradient of Meis homeodomain transcription factors along the mouse limb bud proximo-distal (PD) axis antiparallel to and shaped by the inhibitory action of distal FGF signals. Elimination of Meis results in premature limb distalization and proximalization of PD segmental borders, and phocomelia. Our results show that Meis transcription factors interpret FGF signaling to convey positional information along the limb bud PD axis. These findings establish a new model for the generation of PD identities in the vertebrate limb and provide a molecular basis for the interpretation of FGF signal gradients during axial patterning (Sci Adv, 2020, PMID: 32537491) . In ongoing work, we are defining the role of distal FGF signals in generating the pattern and differentiation of the pelvis in the hindlimb. We had previously demonstrated that these FGF signals are downstream of the BMP receptor, 1a (Development, 2007, PMID: 17537800) . We are now using sophisticated genetics and cutting edge imagery of gene expression to define which FGFs are responsible for forming this most proximal element and initiating limb formation.