Role of BMP and FGF signaling during limb development

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）。在目前的工作中，我们发现Meis同源结构域转录因子沿小鼠肢体芽近端远端（PD）轴的梯度与远端FGF信号的抑制作用反平行并形成。Meis的消除会导致过早的肢体远端和近端PD节段边界，以及光秃。我们的研究结果表明，Meis转录因子解释FGF信号，沿肢体芽PD轴传递位置信息。这些发现为脊椎动物肢体PD身份的产生建立了新的模型，并为轴向模式过程中FGF信号梯度的解释提供了分子基础（Sci Adv, 2020, pmiid: 32537491）。在正在进行的工作中，我们正在确定远端FGF信号在后肢骨盆形成模式和分化中的作用。我们之前已经证明这些FGF信号位于BMP受体1a的下游（Development, 2007, pmiid: 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确定哪些fgf负责形成最近端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.