Role of BMP and FGF signaling during limb development

在以前的工作中，我们产生了一种新的模型，其中表面外胚层必须接收BMP信号，导致FGFs的下调，这反过来又诱导底层间充质细胞凋亡的遗传证据。因此，我们证明BMPs通过调节FGF信号间接控制程序性细胞死亡。然而，重要的是要强调，这一认识并不排除BMP信号在控制发育肢体细胞死亡中的直接作用。因此，我们通过研究BMP和FGF信号传导在肢体发育的各个方面的作用来扩展这些研究，使用在发育肢体的特定区域表达Cre的小鼠品系。例如，检验BMPs作为细胞死亡的直接效应物的假设的唯一方法是仅在经历细胞死亡的谱系中抑制BMPs受体，而不影响附近细胞中的FGF表达。我们已经实现了这一点，使用新的Cre线，使Cre介导的基因失活在这些谱系。利用这些细胞系，我们已经确定BMP是细胞死亡的直接效应物（Dev Biol.411：266-76）。在目前的工作中，我们表明，梯度的Meis同源结构域转录因子沿着小鼠肢芽近端-远端（PD）轴反平行于远端FGF信号的抑制作用和形状。Meis的消除导致PD节段边界的过早肢体远侧化和近侧化以及短肢畸形。我们的研究结果表明，Meis转录因子解释FGF信号传递位置信息沿着肢芽PD轴。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，并为轴向模式化期间FGF信号梯度的解释提供了分子基础（Sci Adv，2020，PMID：32537491）。在正在进行的工作中，我们正在定义远端FGF信号在后肢骨盆形成模式和分化中的作用。我们先前已经证明这些FGF信号是BMP受体1a的下游（Development，2007，PMID：17537800）。我们现在正在使用复杂的遗传学和基因表达的尖端图像来定义哪些FGF负责形成这个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.