Department of Developmental Biology and Howard Hughes Medical Institute, Lorry I. Lokey Stem Cell Research Building, Stanford University, Stanford, CA 94305, USA.
Dev Biol. 2012 Sep 1;369(1):101-14. doi: 10.1016/j.ydbio.2012.06.020. Epub 2012 Jul 4.
Embryonic development is controlled by a small set of signal transduction pathways, with vastly different phenotypic outcomes depending on the time and place of their recruitment. How the same molecular machinery can elicit such specific and distinct responses, remains one of the outstanding questions in developmental biology. Part of the answer may lie in the high inherent genetic complexity of these signaling cascades, as observed for the Wnt-pathway. The mammalian genome encodes multiple Wnt proteins and receptors, each of which show dynamic and tightly controlled expression patterns in the embryo. Yet how these components interact in the context of the whole organism remains unknown. Here we report the generation of a novel, inducible transgenic mouse model that allows spatiotemporal control over the expression of Wnt5a, a protein implicated in many developmental processes and multiple Wnt-signaling responses. We show that ectopic Wnt5a expression from E10.5 onwards results in a variety of developmental defects, including loss of hair follicles and reduced bone formation in the skull. Moreover, we find that Wnt5a can have dual signaling activities during mouse embryonic development. Specifically, Wnt5a is capable of both inducing and repressing β-catenin/TCF signaling in vivo, depending on the time and site of expression and the receptors expressed by receiving cells. These experiments show for the first time that a single mammalian Wnt protein can have multiple signaling activities in vivo, thereby furthering our understanding of how signaling specificity is achieved in a complex developmental context.
胚胎发育受一小部分信号转导途径的控制,其表型结果因募集途径的时间和位置而异。相同的分子机制如何产生如此具体和独特的反应,仍然是发育生物学中的一个悬而未决的问题。答案的一部分可能在于这些信号级联的固有遗传复杂性,正如 Wnt 途径所观察到的那样。哺乳动物基因组编码多种 Wnt 蛋白和受体,它们在胚胎中表现出动态和严格控制的表达模式。然而,这些组件在整个生物体中的相互作用方式仍不清楚。在这里,我们报告了一种新型诱导型转基因小鼠模型的产生,该模型允许在时空上控制 Wnt5a 的表达,Wnt5a 是一种参与许多发育过程和多种 Wnt 信号反应的蛋白质。我们表明,从 E10.5 开始异位表达 Wnt5a 会导致多种发育缺陷,包括毛囊丧失和颅骨骨形成减少。此外,我们发现 Wnt5a 在小鼠胚胎发育过程中具有双重信号活性。具体而言,Wnt5a 能够在体内诱导和抑制β-catenin/TCF 信号,具体取决于表达的时间和部位以及接收细胞表达的受体。这些实验首次表明,单个哺乳动物 Wnt 蛋白在体内可以具有多种信号活性,从而进一步了解在复杂的发育环境中如何实现信号特异性。