Non-nuclear Pool of Splicing Factor SFPQ Regulates Axonal Transcripts Required for Normal Motor Development.
Non-nuclear Pool of Splicing Factor SFPQ Regulates Axonal Transcripts Required for Normal Motor Development.
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DOI：
10.1016/j.neuron.2017.03.026
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发表时间：
2017-04-19
期刊：
影响因子：
16.2
通讯作者：
Houart C
中科院分区：
文献类型：
--
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
最近的进展揭示了RNA加工的复杂性及其与人类疾病的关联。在这里，我们揭示了这种复杂性的一个新方面。普遍剪接因子SFPQ功能完全丧失影响斑马鱼运动神经元自主分化。除了其核定位，蛋白质出乎意料地定位于运动轴突。SFPQ的胞质版本废除运动轴突缺陷，拯救关键的成绩单，并恢复瘫痪的sfpq无效突变体的运动性，表明在运动轴突中的非核处理作用。影响保守的卷曲螺旋结构域的新变体，到目前为止只在fALS外显子组中发现，特别影响SFPQ定位在轴突中的能力。它们广泛地拯救斑马鱼突变体的形态和运动性，但改变运动轴突形态，表明轴突SFPQ的功能要求。总之，我们揭示了剪接因子SFPQ在运动发育中的轴突功能，并强调了卷曲螺旋结构域在这一过程中的重要性。SFPQ剪接因子存在于运动轴突中非核SFPQ能够驱动轴突成熟和连接性轴突SFPQ的丧失影响轴突形态该蛋白的卷曲螺旋结构域对于非核定位是重要的。证明剪接因子SFPQ的非核库是正常运动发育所必需的，通过局部mRNA的维持或加工。SFPQ的卷曲螺旋域是轴突定位所必需的。他们的发现可能对理解人类运动神经元疾病产生重要影响。
Recent progress revealed the complexity of RNA processing and its association to human disorders. Here, we unveil a new facet of this complexity. Complete loss of function of the ubiquitous splicing factor SFPQ affects zebrafish motoneuron differentiation cell autonomously. In addition to its nuclear localization, the protein unexpectedly localizes to motor axons. The cytosolic version of SFPQ abolishes motor axonal defects, rescuing key transcripts, and restores motility in the paralyzed sfpq null mutants, indicating a non-nuclear processing role in motor axons. Novel variants affecting the conserved coiled-coil domain, so far exclusively found in fALS exomes, specifically affect the ability of SFPQ to localize in axons. They broadly rescue morphology and motility in the zebrafish mutant, but alter motor axon morphology, demonstrating functional requirement for axonal SFPQ. Altogether, we uncover the axonal function of the splicing factor SFPQ in motor development and highlight the importance of the coiled-coil domain in this process. SFPQ splicing factor is present in motor axons Non-nuclear SFPQ is able to drive axon maturation and connectivity Loss of axonal SFPQ affects axonal morphology Coiled-coil domain of the protein is important for non-nuclear localization Thomas-Jinu et al. demonstrate that a non-nuclear pool of the splicing factor SFPQ is necessary for normal motor development, through local mRNA maintenance or processing. SFPQ’s coiled-coil domain is required for axonal localization. Their findings may have an important impact in understanding human motor neuron disorders.