Functional analysis of alkylglycerol monooxygenase; an unexpected modulator of Wnt signalling and embryogenesis

总的来说：一个胚胎要正常发育，或者一个成年人要正常运作，细胞之间需要相互沟通。这种交流告诉细胞它们应该做什么。Wnt信号通路是一种细胞通信系统，在胚胎发育过程中告诉细胞如何行为起着重要作用。Wnt信号受损会导致出生缺陷，并导致许多成人疾病，包括癌症。因此，了解Wnt通路的工作原理非常重要，这样我们就可以发现控制它的方法，并有可能找到治疗疾病的新方法。细胞可以对Wnt通路中的蛋白质进行修饰以控制其功能。几乎Wnt信号通路的每一步都是由小脂质的附着或去除来调节的。然而，尽管这些脂质修饰很重要，但我们对它们如何发生以及它们如何控制Wnt信号传导的理解仍然非常有限。在某种程度上，这是因为很难找到产生这些修饰的基因。我们最近发现，一种名为amgo的基因是Wnt信号的调节器，是胚胎心脏正常发育所必需的，它编码已知的唯一一种切割特定类型脂质（称为醚脂质）的酶。我们也有初步证据表明，agmo在头部、大脑和肌肉的发育中起着重要作用。此外，在超过25例agmo突变患者中发现了神经、心脏、肌肉和面部异常的组合。然而，我们仍然对agmo的功能知之甚少，也不知道是否需要脂质来形成胚胎。在这个项目中，我们将研究agmo在Wnt信号传导和发展中的作用。在Objective 1中，我们将确定agmo对于头部、大脑和肌肉的正常发育是否真的是必需的？我们将通过降低蝌蚪和小鸡胚胎中的agmo水平，并使用最先进的成像和分子生物学分析来观察这些结构的发育是否被改变。在目标2中，我们将研究agmo如何影响Wnt信号通路。特别是，我们将使用一系列分子实验来发现途径中需要agmo的步骤，以及它调节Wnt信号传导的机制。最后，在目标3中，我们将精确测量agmo消耗如何影响胚胎脂质代谢。一旦我们确定了agmo耗尽的青蛙的途径哪里出错，我们将测试我们是否可以纠正这种代谢问题，以防止Wnt信号问题和出生缺陷。总之，这些实验将揭示Wnt通路的一个新的和强大的调节器是如何工作的。我们认为我们的发现有可能改变我们对Wnt通路的理解，我们希望为基础和治疗研究开辟新的途径。

The big picture: for an embryo to develop normally, or an adult to function correctly, cells need to communicate with each other. This communication tells cells what they should do. The Wnt signalling pathway is a cellular communication system that plays important roles in telling cells how to behave during development of an embryo. Impaired Wnt signalling causes birth defects and contributes to numerous adult diseases, including cancers. As such, it is important we understand how the Wnt pathway works so that we can discover ways to control it and potentially find new ways to treat disease.Proteins in the Wnt pathway can be modified by cells to control how they function. Almost every step in the Wnt signalling pathway is regulated by the attachment or removal of small lipids. However, despite the importance of these lipid modifications, our understanding of how they occur and how they control Wnt signalling remains very limited. In part this is because it is difficult to find the genes making these modifications. We recently discovered that a gene named amgo, which encodes the only enzyme known to cut a particular type of lipids (called ether lipids), is a regulator of Wnt signalling and is required for normal development of the embryonic heart. We also have preliminary evidence that agmo plays an important role in development of the head, brain and muscles. Furthermore, combinations of neural, cardiac, muscle and facial abnormalities have been identified in over 25 human patients with mutations in agmo. However, we still know very little about how agmo functions, or how ether lipids are needed to form an embryo. In this project we will investigate the role of agmo in Wnt signalling and development.In Objective 1, we will determine whether agmo is really required for normal development of the head, brain and muscles? We will do this by decreasing agmo levels in tadpoles and chick embryos and using state of the art imaging and molecular biology assays to see if development of these structures is altered.In Objective 2, we will investigate how agmo affects the Wnt signalling pathway. In particular, we will use a series of molecular experiments to discover the step in the pathway where agmo is needed, and the mechanism by which it regulates Wnt signalling.Finally, in Objective 3 we will precisely measure how agmo depletion is affecting embryonic lipid metabolism. Once we have identified where the pathway goes wrong in agmo depleted frogs, we will then test whether we can correct this metabolic problem to prevent the Wnt signalling problems and birth defects.Together, these experiments will reveal how a new and powerful regulator of the Wnt pathway works. We think that our discoveries have the potential to transform our understanding of the Wnt pathway, and we hope to open up new avenues of basic and therapeutic research.