Role of BMP and FGF signaling during limb development

BMP 和 FGF 信号在肢体发育过程中的作用

• 批准号: 10702370
• 负责人: MARK B LEWANDOSKI
• 金额: $ 37.78万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702370
• 关键词: Address; Adult; Affect; Apoptosis; Behavior; Biology; Bone Morphogenetic Proteins; Cell Death; Cells; Cellular biology; Data; Development; Disease; Distal; Down-Regulation; Effector Cell; Elements; Embryo; Embryonic Development; Family; Fibroblast Growth Factor; Gastrointestinal Neoplasms; Gene Expression; Gene Silencing; Generations; Genetic; Goals; Growth; Heart; Hindlimb; Imagery; Limb Bud; Limb Development; Limb structure; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mesenchyme; Metastatic Neoplasm to the Bone; Modeling; Molecular; Mus; Normal Cell; Pathway interactions; Pattern; Pelvis; Phocomelia; Protein Family; Role; Signal Transduction; Signaling Molecule; Signaling Protein; Surface Ectoderm; Testing; Work; bone morphogenetic protein receptors; breast cancer progression; homeodomain; insight; novel; premature; transcription factor; tumor

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.

在之前的工作中，我们为一种新模型提供了遗传证据，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 BMP 通过调节 FGF 信号传导来间接控制程序性细胞死亡。然而，需要强调的是，这一见解并不排除 BMP 信号在控制发育中肢体细胞死亡中的直接作用。因此，我们通过使用在发育肢体特定区域表达 Cre 的小鼠系来研究 BMP 和 FGF 信号传导在肢体发育各个方面的作用，从而扩展了这些研究。例如，检验 BMP 作为细胞死亡直接效应器的假设的唯一方法是仅使经历细胞死亡的谱系中的 BMP 受体失活，而不影响附近细胞中的 FGF 表达。我们使用新的 Cre 品系实现了这一目标，该品系允许 Cre 介导的基因失活。通过这些细胞系，我们确定 BMP 是细胞死亡的直接效应物 (Dev Biol. 411: 266-76)。在当前的工作中，我们发现沿着小鼠肢芽近远端（PD）轴的 Meis 同源域转录因子的梯度与远端 FGF 信号的抑制作用反向平行并由其形成。 Meis 的消除会导致肢体过早远端化和 PD 节段边界近端化，以及海肢症。我们的结果表明 Meis 转录因子解释 FGF 信号传导以沿肢芽 PD 轴传递位置信息。这些发现为脊椎动物肢体中 PD 身份的生成建立了一个新模型，并为轴向模式形成过程中 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 信号在后肢骨盆生成模式和分化中的作用。我们之前已经证明这些 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最先进的基因表达图像来定义哪些 FGF 负责形成这种最近端元素并启动肢体形成。