ROLE OF MORPHOGENETIC PROTEINS IN EMBRYOGENESIS AND TISSUE REGENERATION

我们的主要目标是识别和定义可用于修复因创伤、肿瘤或其他病理损伤的组织或结构的蛋白质的作用。我们已经鉴定了十几种新的蛋白质。其中两种诱导软骨的形成，一种诱导骨和造血组织的形成，一种在确定胚胎发育的整体模式中起关键作用，另外三种功能未知。其中一种蛋白Frzb是Wnt生长因子致癌基因信号传导的分泌抑制剂，是一个不断增长的相关蛋白家族的原型。揭示了Wnt和骨形态发生蛋白（BMP）家族的分泌生长因子与这些蛋白的分泌拮抗剂之间的关键反馈相互作用。发现BMP - 4和7、Wnt-8、BMP拮抗剂chordin和noggin以及Wnt拮抗剂Frzb的局部表达建立了形成脊椎动物肌肉最早前体的形态发生场。这些蛋白的表达模式之间的关系似乎维持了Wnt-8和bmp - 4&7途径控制组织命运的动态平衡。dbl癌基因在发育中的中枢神经系统中以一种复杂的模式表达，表明这种鸟嘌呤核苷酸交换蛋白可能在神经分化中具有特定的功能。几个新的基因被鉴定出来，包括哺乳动物胸腺生成素的可能同源物，在原肠胚形成过程中开始表达。目前，我们正在利用热带非洲爪蟾（Silurana）模型促进或可能的实验范式，进一步定义这些蛋白质的功能。这个物种是一个真正的二倍体，因此经典的遗传研究可以添加到已经在非洲爪蟾中使用的实验库中。此外，还可以探索创造功能丧失或其他突变体的策略，这些突变体很难在假四足体X. laevis中进行设计。

Our primary goal is to identify and define the actions of proteins that can be used to repair tissues or structures that have been damaged by trauma, neoplasia, or other pathology. We have identified over a dozen novel proteins. Two of these induce the formation of cartilage, one induces the formation of bone and hematopoietic tissue, one plays a key role in defining the overall pattern of the developing embryo, and three others have unknown functions. One of these proteins, Frzb, is a secreted inhibitor of signaling by the Wnt growth factor oncogenes, and is the prototype of a growing family of related proteins. Key feedback interactions between secreted growth factors belonging to the Wnt and Bone Morphogenetic Protein (BMP) families and secreted antagonists of these proteins were elucidated. Localized expression of BMPs 4&7, Wnt-8, the BMP antagonists chordin and noggin, and the Wnt antagonist Frzb were found to establish the morphogenetic field giving rise to the earliest precursors of vertebrate muscle. The relationship of expression pattern of these proteins appears to maintain a dynamic balance between Wnt-8 and BMPs 4&7 pathways that controls tissue fate. The dbl oncogene was found to be expressed in a complex pattern within the developing central nervous system, suggesting that this guanine nucleotide exchange protein may have specific functions in neural differentiation. Several novel genes were identified, including a possible homologue of mammalian thymopoietin that begins to be expressed during gastrulation. Presently, we are undertaking to define the functions of these proteins further using experimental paradigms either facilitated or made possible by the Xenopus (Silurana) tropicalis model. This species is a true diploid, so that classical genetic studies can be added to the repertoire of experiments already in use in Xenopus laevis. Moreover, strategies to create loss-of-function or other mutants, which would be difficult to engineer in the pseudotetraloid X. laevis, can also be explored.