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.

运动神经元疾病是影响运动神经元的一组神经病理性，这些病理是控制基本的自愿肌肉活动的细胞，例如步行，呼吸和说话。通常，来自大脑中神经元的信息会传播到脑干和脊髓中的神经元，并在其中告知肌肉收缩。当运动神经元和肌肉之间的信号中断时，后者逐渐削弱，抽搐异常，最后停止收缩。在过去的十年中，在识别突变诱导（或增加）产后或产后运动神经元功能障碍的基因方面取得了很多进展。这些基因的鉴定导致出乎意料的发现，即大多数运动病理是由神经元中受限制的生物学过程中的异常引起的。但是，我们尚不了解这些过程中特定变化的性质以及这些如何触发神经元异常。这些过程之一是mRNA加工和运输，这是转化为成熟的使者RNA并将其转运到神经元的局部区域的机制，并将其转化为特定的蛋白质。主要申请人最近开发了斑马鱼遗传模型，以研究剪接因子在成人生活中运动神经元发展和维持中的作用。通过一组特定的斑马鱼突变体，申请人已经确定了在复杂神经元中本地分发信息所需的新机制。该机制中的这个关键参与者是称为剪接因子的蛋白质，它们正在将前MRNA（Messenger RNA的草稿版本）转化为成熟的Messenger RNA。已知这群分子在核中活跃。但是，申请人发现，其中至少两个（称为SFPQ和SNRNP70）也活跃在运动神经元的轴突中，这是电动机神经元的一部分，将信息传递到肌肉中。此研究计划建议 - 使用此新的新的斑马鱼模型在没有轴突剪接因子的情况下驱动运动功能障碍的生物学过程。拟议的研究将使对细胞核之外的剪接因子的作用有新的了解。它还将确定一种新型的分子网络驱动运动障碍，并发现一种特定的机制，使很长而复杂的神经元可以做出非常受控的局部决策。

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

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

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

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

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