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

神经连通性和突触可塑性被认为是高级认知功能、学习、灵巧等的基础，也是自闭症、精神分裂症、运动神经元和神经肌肉疾病等疾病的缺陷。控制大脑和肌肉正常神经元连接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鉴定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，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Arkadia2，它专门存在于大脑和脊髓的神经元中。我们培养了缺乏Arkadia2的小鼠，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，他们变瘦，死于进行性神经肌肉无力，无法进食和呼吸的症状。这些症状类似于人类患有运动神经元疾病，这是一种使人衰弱和致命的疾病。arkadi2和最有可能的arkadi2是像tgf - β /BMP信号级联这样的大型基因网络的一部分。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的生长（这是神经元与肌肉细胞连接以交流和控制运动的结构）。因此，Arkadia2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信缺陷。然而，该基因网络在哺乳动物神经肌肉突触中的作用尚不清楚。在这里，我们建议分析这些小鼠的神经元缺陷，并研究Arkadia2蛋白如何与tgf β /BMP基因网络的其他蛋白相互作用。我们的研究将为正常的神经元发育提供有价值的见解，并为了解与肌肉神经支配和大脑布线相关的疾病的发病机制提供一个系统。此外，这些研究将为药物和治疗方法的开发提供动物模型。

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.