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: 10014392
• 负责人: MARK B LEWANDOSKI
• 金额: $ 40.88万
• 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/10014392
• 关键词: Address; Adult; Affect; Animals; Apoptosis; Behavior; Biology; Bone Morphogenetic Proteins; Cell Death; Cells; Cellular biology; Data; Development; Digit structure; Disease; Distal; Down-Regulation; Effector Cell; Elements; Embryo; Embryonic Development; Excision; Family; Fibroblast Growth Factor; Gastrointestinal Neoplasms; Gene Silencing; Genetic; Goals; Growth; Heart; Internet; Lead; Learning; Limb Bud; Limb Development; Limb structure; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mesenchymal; Mesenchyme; Metastatic Neoplasm to the Bone; Modeling; Molecular; Mus; Normal Cell; Pathway interactions; Pattern; Population; Protein Family; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Skeleton; Structure; Surface Ectoderm; Testing; Work; bone morphogenetic protein receptors; breast cancer progression; insight; novel; progenitor; skeletal; tumor

In current work, we are studying the role of BMP signaling as effectors of normal programmed cell death that occurs in mesenchymal interdigit cells, thus removing them and sculpting the final digit pattern in animals that are born without webbed limbs. 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 a serendipitous discovery, we have found that removal of a BMP signal to the limb bud interdigit zone rescues the requirement for a BMP signal to the digit region of the developing limb. Our efforts to understand this rescue may lead to a fundamental understanding of patterning in the developing limb. In another study, we have uncovered an important node of signaling between FGFs and BMP that is essential for normal development of the limb skeleton. Our previous work demonstrates that specific FGFs, secreted from a distal structure in the limb bud, regulate the normal outgrowth and patterning of the limb. In current work, we are generating genetic evidence that BMP signaling to the progenitor population of the skeletal elements regulates this FGF signal by controlling the expression of an FGF antagonist. This linking of the two signaling pathways is not only a unique insight into how the limb is patterned but may provide a model for how the two pathways interact in other developmental contexts or during cancer.

在目前的工作中，我们正在研究BMP信号传导作为间充质趾间细胞中发生的正常程序性细胞死亡的效应器的作用，从而去除它们并在出生时没有蹼状肢的动物中塑造最终的数字模式。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）。在一个偶然的发现中，我们已经发现，去除肢芽趾间区的BMP信号可以挽救发育中肢体的趾区对BMP信号的需求。我们努力理解这种拯救，可能会导致对发育中肢体的模式的基本理解。在另一项研究中，我们发现了FGF和BMP之间的一个重要信号节点，这对肢体骨骼的正常发育至关重要。我们以前的工作表明，特定的FGF，从肢芽的远端结构分泌，调节正常的生长和肢体的图案。在目前的工作中，我们正在产生遗传学证据，BMP信号传导到骨骼元件的祖细胞群体通过控制FGF拮抗剂的表达来调节FGF信号。这两种信号通路的联系不仅是对肢体如何形成的独特见解，而且可能为这两种通路在其他发育环境或癌症期间如何相互作用提供模型。