Novel Function of Splicing factors in Establishment and Maintenance of Neuronal Connectivity

运动神经元疾病是一组影响运动神经元的神经系统疾病，运动神经元是控制基本随意肌活动（如行走、呼吸和说话）的细胞。正常情况下，来自大脑神经元的信息被传递到脑干和脊髓的神经元，在那里它们通知肌肉收缩。当运动神经元和肌肉之间的信号中断时，肌肉会逐渐减弱，不正常地抽搐，最终停止收缩。在过去的十年里，在识别哪些突变会诱发（或增加）产前或产后运动神经元功能障碍的基因方面取得了很大的进展。这些基因的鉴定导致了一个意想不到的发现，即大多数运动病理是由神经元中一组有限的生物过程的异常引起的。然而，我们还不了解这些过程中具体变化的本质，以及这些变化是如何引发神经元异常的。其中一个过程是mRNA的加工和转运，即转录本的草稿版本转化为成熟的信使RNA并转运到神经元的局部区域，在那里它们被翻译成特定的蛋白质。首席申请人最近开发了斑马鱼遗传模型，以研究剪接因子在成年期运动神经元发育和维持中的作用。通过一组特殊的斑马鱼突变体，申请者已经确定了一种新的机制，需要在复杂的神经元中局部分配信息。这种机制中的关键角色是一种叫做剪接因子的蛋白质，它将pre-mRNA（信使RNA的雏形）转化为成熟的信使RNA。已知这组分子在原子核中是活跃的。然而，申请者发现其中至少有两个（称为SFPQ和snRNP70）在运动神经元的轴突中也很活跃，运动神经元的轴突是将信息传递给肌肉的部分。本研究计划建议-使用这种新的斑马鱼模型来成像和理解在缺乏轴突剪接因子的情况下驱动运动功能障碍的生物过程。-了解SFPQ和snRNP70与轴突rna的作用，以及它们与哪些蛋白质相互作用以实现这些作用。我们期望所提出的研究将带来对细胞核外剪接因子作用的新认识。它还将确定一种驱动运动损伤的新型分子网络，并揭示一种特定的机制，允许非常长和复杂的神经元做出非常受控的局部决定。

Motor neuron disorders are a group of neurological pathologies that affects motor neurons, the cells that control essential voluntary muscle activity such as walking, breathing, and speaking. Normally, messages from neurons in the brain are transmitted to neurons in the brain stem and spinal cord where they inform muscles to contract. When there are disruptions in the signals between the motor neurons and the muscles, the latter progressively weaken, twitches abnormally and finally stop contracting. In the last decade, a lot of progress has been made in identifying genes in which mutations induce (or increase the chance of) pre- or post-natal motor neuron dysfunction. The identification of these genes lead to the unexpected finding that most motor pathologies arise from abnormalities in a restricted set of biological processes in the neurons. However, we don't yet understand the nature of the specific changes made in these processes and how these trigger neuronal abnormalities. One of these processes is mRNA processing and transport, the mechanism by which draft versions of transcripts are transformed into mature messenger RNA and transported into local areas of the neurons where they are translated into specific proteins. The lead applicant has very recently developed zebrafish genetic models to study the role of splicing factors in motor neuron development and maintenance during adult life. Through a set of particular zebrafish mutants, the applicants have identified a new mechanism required to distribute information locally in complex neurons. This key actors in this mechanism are proteins called splicing factors, that are transforming the pre-mRNA (draft version of a messenger RNA) into a mature messenger RNA. This group of molecules is known to be active in the nucleus. However, the applicants found that at least two of these (called SFPQ and snRNP70) are also active in the axon of motor neurons, the part of the motor neuron that transfer the information to the muscle.This research programme proposes - To use this new zebrafish models to image and understand the biological process driving motor dysfunction in absence of axonal splicing factors.- To understand what are SFPQ and snRNP70 doing with RNAs in the axon, and which are the proteins their interact with to achieve these roles.We expect that the proposed research will bring a novel understanding of the role of splicing factors outside of the cell nucleus. It will also identify a novel molecular network driving motor impairment and uncover a specific mechanism allowing very long and complex neurons to take very controlled local decisions.