Fragile X mental retardation protein regulates skeletal muscle stem cell activity by regulating the stability of Myf5 mRNA.
Fragile X mental retardation protein regulates skeletal muscle stem cell activity by regulating the stability of Myf5 mRNA.
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DOI：
10.1186/s13395-017-0136-8
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发表时间：
2017-09-07
期刊：
影响因子：
4.9
通讯作者：
Crist C
中科院分区：
文献类型：
--
作者：
Fujita R;Zismanov V;Jacob JM;Jamet S;Asiev K;Crist C
成体组织的再生依赖于准备进入分化程序的成体干细胞，同时通常保持静止。在小鼠骨骼肌中，这些特征被多种翻译控制机制协调，这些机制确保启动的肌肉干细胞(MuSCs)不被激活。在静止的MuSCs中，由microRNA-31和脆性X智力低下蛋白(FMRP)介导的Myf5翻译的可逆microRNA沉默说明了这一概念。在这项工作中，我们利用FMRP基因敲除(Fmr1FMRP)小鼠来支持FMRP在维持−/−干细胞属性中的作用。我们比较了急性损伤和植入后的体内和体外培养过程中MuSCs的活性。我们使用RNA免疫沉淀和3‘非编码区多聚腺嘌呤(PolyA)长度分析来评估FMRP对生肌调节因子转录本稳定性的影响。我们证明了RNA结合的FMRP是维持MUSC池所必需的。更具体地说，肌肉干细胞的干细胞特性需要FMRP，包括启动肌肉生成计划的MUSC能力，它们的自我更新，以及它们高效再生肌肉的能力。我们提供的证据表明，FMRP对MUSC活性的调节部分是通过FMRP直接结合Myf5转录本的能力和影响Myf5去烯化的速度来实现的。我们的结果提供了进一步的证据，支持RNA结合蛋白的转录后沉默平台在维持成体干细胞的干性属性中的作用。此外，在缺乏Fmr1的情况下，去调节的MUSC活性可能与脆性X综合征有关，该综合征与婴儿时期的肌肉低张症有关。
Regeneration of adult tissues relies on adult stem cells that are primed to enter a differentiation program, while typically remaining quiescent. In mouse skeletal muscle, these features are reconciled by multiple translational control mechanisms that ensure primed muscle stem cells (MuSCs) are not activated. In quiescent MuSCs, this concept is illustrated by reversible microRNA silencing of Myf5 translation, mediated by microRNA-31 and fragile X mental retardation protein (FMRP). In this work, we take advantage of FMRP knockout (Fmr1 −/−) mice to support the role for FMRP in maintaining stem cell properties of the MuSC. We compare the activity of MuSCs in vivo after acute injury and engraftment, as well as ex vivo during culture. We use RNA immunoprecipitation and 3’UTR poly-adenine (poly(A)) length assays to assess the impact of FMRP on the stability of transcripts for myogenic regulatory factors. We show that RNA-binding FMRP is required to maintain the MuSC pool. More specifically, FMRP is required for stem cell properties of muscle stem cells, which include MuSC capacity to prime the myogenic program, their self-renewal, and their capacity to efficiently regenerate muscle. We provide evidence that FMRP regulation of MuSC activity occurs in part by the capacity of FMRP to directly bind Myf5 transcripts and impact rates of Myf5 deadenylation. Our results provide further evidence supporting a role for post-transcriptional silencing platforms by RNA-binding proteins in maintaining stemness properties of adult stem cells. In addition, deregulated MuSC activity in the absence of Fmr1 may have implications for fragile X syndrome, which is associated with muscle hypotonia during infancy.
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影响因子：
--
作者：
KELLY, AM
通讯作者：
KELLY, AM
DOI：
10.1002/ajmg.1320380267
发表时间：
1991-02-01
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
WISNIEWSKI, KE;SEGAN, SM;RUDELLI, RD
通讯作者：
RUDELLI, RD
影响因子：
4.9
作者：
Pawlikowski B;Pulliam C;Betta ND;Kardon G;Olwin BB
通讯作者：
Olwin BB
PAX3和PAX7在成年肌肉祖细胞中具有明显的重叠功能。
影响因子：
7.8
作者：
Relaix, Frederic;Montarras, Didier;Zaffran, Stephane;Gayraud-Morel, Barbara;Rocancourt, Didier;Tajbakhsh, Shahragim;Mansouri, Ahmed;Cumano, Ana;Buckingham, Margaret
通讯作者：
Buckingham, Margaret
影响因子：
10.5
作者：
Caudy, AA;Myers, M;Hammond, SM
通讯作者：
Hammond, SM