Functional analysis of Arkadia2 a novel ubiquitin ligase expressed specifically in neurons

Arkadia2 的功能分析，一种在神经元中特异性表达的新型泛素连接酶

• 批准号: BB/G00577X/1
• 负责人: Vasso Episkopou
• 金额: $ 41.61万
• 依托单位: Medical Research Council
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FG00577X%2F1
• 关键词: Functional; analysis; Arkadia2; novel; ubiquitin

Neuronal connectivity and synaptic plasticity are believed to underlie higher cognitive functions, learning, dexterity, etc, and to be defective in diseases like autism schizophrenia, motor neuron and neuromuscular diseases. Genetic factors that control normal neuronal wiring of the brain and the muscles remain largely unknown. Genetically engineered mice are ideal for the identification and study of gene function in the context of the whole organism, and the understanding of the normal development, the architecture and function of complex organs and systems such as the brain and neurons. We previously discovered Arkadia, a novel factor essential for embryonic development in mice. We have now identified a homologue of Arkadia, here termed Arkadia2, which is present specifically in neurons of the brain and spinal cord. We generated mice deficient for Arkadia2 and found that they exhibit abnormal limb movement and posture. During the first 2 weeks after birth they become thinner and die with symptoms of progressive neuromuscular weakness with inability to feed and breath. These symptoms are similar to humans with motor neuron disease a debilitating and lethal disorder. Arkadia and most likely Arkadia2 are part of large networks of genes such as that of the TGFbeta/BMP signalling cascade. Interestingly, in the fruit fly, BMP signalling has been shown to regulate the growth of the neuromuscular synapse (which are the structures that a neuron connects with the muscle cells to communicate and control movement). It is therefore very likely that the phenotype of the Arkadia2 mutant mice is similar and due to defective muscle innervation and communication. However, the role of this gene network in mammalian neuromuscular synapse remains unknown. Here we propose to analyse the neuronal defects in these mice and study how Arkadia2 protein interacts with other proteins of the TGFbeta/BMP gene network. Our research will provide valuable insights to normal neuronal development and a system to understand the pathogenesis of diseases associated with muscle innervation and brain wiring. In addition, these studies will provide an animal model for the development of drugs and therapeutic approaches.

神经元连接和突触可塑性被认为是高级认知功能、学习、灵活性等的基础，并且在自闭症、精神分裂症、运动神经元和神经肌肉疾病等疾病中是有缺陷的。控制大脑和肌肉的正常神经元布线的遗传因素在很大程度上仍然未知。基因工程小鼠是在整个生物体背景下识别和研究基因功能的理想选择，也是理解正常发育、复杂器官和系统（如大脑和神经元）的结构和功能的理想选择。我们之前发现了Arkadia，这是一种对小鼠胚胎发育至关重要的新因子。我们现在已经确定了Arkadia的同源物，这里称为Arkadia 2，它特别存在于大脑和脊髓的神经元中。我们产生了Arkadia 2缺陷小鼠，发现它们表现出异常的肢体运动和姿势。在出生后的前两周，他们变得更瘦，并死于渐进性神经肌肉无力的症状，无法进食和呼吸。这些症状类似于人类运动神经元疾病，一种使人衰弱和致命的疾病。Arkadia和最有可能的Arkadia 2是大型基因网络的一部分，如TGF β/BMP信号级联。有趣的是，在果蝇中，BMP信号已被证明可以调节神经肌肉突触（神经元与肌肉细胞连接以进行通信和控制运动的结构）的生长。因此，Arkadia 2突变小鼠的表型很可能是相似的，并且是由于肌肉神经支配和通讯缺陷所致。然而，这个基因网络在哺乳动物神经肌肉突触中的作用仍然未知。在这里，我们建议分析这些小鼠的神经元缺陷，并研究Arkadia 2蛋白如何与TGF β/BMP基因网络的其他蛋白相互作用。我们的研究将提供有价值的见解，正常的神经元发育和系统，以了解与肌肉神经支配和大脑布线相关的疾病的发病机制。此外，这些研究将为药物和治疗方法的开发提供动物模型。

项目成果

TGF-beta repressors SnoN and Ski are implicated in human colorectal carcinogenesis.

• DOI: 10.3233/clo-2009-0460
• 发表时间: 2009
• 期刊: Cellular oncology : the official journal of the International Society for Cellular Oncology
• 作者: Bravou V;Antonacopoulou A;Papadaki H;Floratou K;Stavropoulos M;Episkopou V;Petropoulou C;Kalofonos H
• 通讯作者: Kalofonos H

Coordination of progenitor specification and growth in mouse and chick spinal cord.

• DOI: 10.1126/science.1254927
• 发表时间: 2014-09-26
• 期刊: Science (New York, N.Y.)
• 作者: Kicheva A;Bollenbach T;Ribeiro A;Valle HP;Lovell-Badge R;Episkopou V;Briscoe J
• 通讯作者: Briscoe J