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，在这种模型中， 外胚层必须接受BMP信号，导致Fgfs的下调，这反过来诱导了BMP信号的产生。 细胞凋亡的基础间质。因此，我们证明BMPs控制程序化细胞， 通过调节FGF信号间接死亡。然而，必须强调的是， 这一观点并不排除BMP信号在控制细胞死亡中的直接作用。 发展肢体。因此，我们通过研究BMP和FGF的作用来扩展这些研究。 使用表达Cre的小鼠系在肢体发育的各个方面的信号传导， 发育肢体的特定区域。例如，检验假设的唯一方法是 骨形成蛋白作为细胞死亡的直接效应物仅在细胞系中抑制骨形成蛋白受体 其经历细胞死亡，而不影响附近细胞中的FGF表达。我们已经取得 这使用新的Cre系，其允许Cre介导的基因在这些谱系中失活。与 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，我们发现Meis同源结构域转录因子的梯度 沿着小鼠肢芽近端-远端（PD）轴，与抑制性神经元反平行，并由抑制性神经元形成。 远端FGF信号的作用。Meis的消除导致肢体过早远端化， PD节段边界的近端化和短肢畸形。我们的研究结果表明， 转录因子解释成纤维细胞生长因子的信号传递位置信息沿着肢体 芽PD轴。这些发现建立了一个新的模型，在PD身份的产生， 脊椎动物肢体，并提供了一个分子基础的FGF信号梯度的解释 在轴向图案化期间（Sci Adv，2020，PMID：32537491）。在正在进行的工作中，我们正在定义 远端成纤维细胞生长因子信号的作用，在产生的模式和分化的骨盆中， 后肢我们先前已经证明这些FGF信号是BMP的下游， 受体，1a（Development，2007，PMID：17537800）。我们现在使用复杂的遗传学， 最前沿的基因表达图像，以确定哪些FGF负责形成这种 最接近的元素和开始肢体形成。

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.