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

剪接因子在神经元连接建立和维持中的新功能

• 批准号: BB/P001599/1
• 负责人: Corinne Houart
• 金额: $ 81.82万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP001599%2F1
• 关键词: Novel; Function; Splicing; factors; Establishment

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.

运动神经元障碍是一组影响运动神经元的神经病理，运动神经元是控制基本的自愿肌肉活动的细胞，如行走、呼吸和说话。正常情况下，来自大脑中神经元的信息被传输到脑干和脊髓中的神经元，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，异常抽搐，最终停止收缩。在过去的十年里，在识别基因突变导致(或增加)出生前或出生后运动神经元功能障碍的基因方面取得了很大进展。对这些基因的识别导致了一个意想不到的发现，即大多数运动病理都是由神经元中一组受限的生物过程中的异常引起的。然而，我们还不知道在这些过程中发生的具体变化的性质，以及这些变化是如何触发神经元异常的。其中一个过程是mRNA的处理和运输，这是一种将转录产物的草稿转化为成熟的信使RNA并运输到神经元局部区域的机制，在那里它们被翻译成特定的蛋白质。牵头申请者最近开发了斑马鱼遗传模型，以研究剪接因子在成年期间运动神经元发育和维持中的作用。通过一组特定的斑马鱼突变体，申请者已经确定了一种在复杂神经元中局部分发信息所需的新机制。这一机制中的关键因素是被称为剪接因子的蛋白质，它将前信使RNA(信使RNA的草案版本)转化为成熟的信使RNA。众所周知，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)也活跃在运动神经元的轴突中，运动神经元的一部分将信息传递到肌肉。这项研究计划建议-使用这个新的斑马鱼模型来成像和理解在没有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在轴突中与RNA做了什么，以及它们与哪些蛋白质相互作用以实现这些作用。我们期待拟议的研究将带来对细胞核外剪接因子作用的新理解。它还将识别驱动运动损伤的新的分子网络，并揭示一种特定的机制，允许非常长的和复杂的神经元做出非常受控制的局部决定。

项目成果

Pineal progenitors originate from a non-neural territory limited by FGF signalling.

松果体祖细胞起源于受 FGF 信号传导限制的非神经区域。

• DOI: 10.1242/dev.171405
• 发表时间: 2019
• 期刊: Development (Cambridge, England)
• 作者: Staudt N

Non-nuclear Pool of Splicing Factor SFPQ Regulates Axonal Transcripts Required for Normal Motor Development.

• DOI: 10.1016/j.neuron.2017.03.026
• 发表时间: 2017-04-19
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Thomas-Jinu S;Gordon PM;Fielding T;Taylor R;Smith BN;Snowden V;Blanc E;Vance C;Topp S;Wong CH;Bielen H;Williams KL;McCann EP;Nicholson GA;Pan-Vazquez A;Fox AH;Bond CS;Talbot WS;Blair IP;Shaw CE;Houart C
• 通讯作者: Houart C

Prematurely terminated intron-retaining mRNAs invade axons in SFPQ null-driven neurodegeneration and are a hallmark of ALS.

• DOI: 10.1038/s41467-022-34331-4
• 发表时间: 2022-11-22
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Taylor, Richard;Hamid, Fursham;Fielding, Triona;Gordon, Patricia M.;Maloney, Megan;Makeyev, Eugene, V;Houart, Corinne
• 通讯作者: Houart, Corinne

Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations.

• DOI: 10.1038/s41598-021-93189-6
• 发表时间: 2021-06-30
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Salam S;Tacconelli S;Smith BN;Mitchell JC;Glennon E;Nikolaou N;Houart C;Vance C
• 通讯作者: Vance C

Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion.

• DOI: 10.1016/j.yjmcc.2018.07.248
• 发表时间: 2018-08
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: Ehsan M;Kelly M;Hooper C;Yavari A;Beglov J;Bellahcene M;Ghataorhe K;Poloni G;Goel A;Kyriakou T;Fleischanderl K;Ehler E;Makeyev E;Lange S;Ashrafian H;Redwood C;Davies B;Watkins H;Gehmlich K
• 通讯作者: Gehmlich K