Dysregulated CRMP Mediates Circadian Deficits in a Drosophila Model of Fragile X Syndrome
Dysregulated CRMP Mediates Circadian Deficits in a Drosophila Model of Fragile X Syndrome
复制标题
CRMP 失调介导脆性 X 综合征果蝇模型的昼夜节律缺陷
DOI：
10.1007/s12264-021-00682-z
复制
发表时间：
2021-04
影响因子：
5.6
通讯作者：
Duan Ranhui
中科院分区：
文献类型：
--
作者：
Zhao Juan;Xue Jin;Zhu Tengfei;He Hua;Kang Huaixing;Jiang Xuan;Huang Wen;Duan Ranhui
脆性X综合征（FXS）是智力残疾的主要遗传原因，其起因于功能性脆性X智力迟钝蛋白（FMRP）的缺乏，FMRP是主要充当翻译调节剂的mRNA结合蛋白。FMRP的缺失导致靶mRNA的失调。FXS的果蝇模型显示出异常的昼夜节律，时钟网络下游的输出通路被破坏。然而，参与昼夜节律调节的FMRP靶点尚未确定。在这里，我们确定了崩溃的反应介质蛋白（CRMP）mRNA作为FMRP的目标。敲除泛神经元CRMP表达改善dfmr1突变果蝇的昼夜节律缺陷和时钟神经元（腹侧神经元）的异常轴突结构。此外，下游输出胰岛素产生细胞中CRMP的特异性减少减弱了异常的昼夜节律行为。分子分析表明，FMRP与CRMP mRNA结合，并负调控其翻译。我们的研究结果表明，CRMP是一个FMRP的目标，并建立一个重要的作用，CRMP在FXS果蝇的昼夜输出。
Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability, resulting from the lack of functional fragile X mental retardation protein (FMRP), an mRNA binding protein mainly serving as a translational regulator. Loss of FMRP leads to dysregulation of target mRNAs. The Drosophila model of FXS show an abnormal circadian rhythm with disruption of the output pathway downstream of the clock network. Yet the FMRP targets involved in circadian regulation have not been identified. Here, we identified collapsing response mediator protein (CRMP) mRNA as a target of FMRP. Knockdown of pan-neuronal CRMP expression ameliorated the circadian defects and abnormal axonal structures of clock neurons (ventral lateral neurons) in dfmr1 mutant flies. Furthermore, specific reduction of CRMP in the downstream output insulin-producing cells attenuated the aberrant circadian behaviors. Molecular analyses revealed that FMRP binds with CRMP mRNA and negatively regulates its translation. Our results indicate that CRMP is an FMRP target and establish an essential role for CRMP in the circadian output in FXS Drosophila.
登录
查看更多内容
DOI：
10.1016/j.tig.2017.07.008
发表时间：
2017-10
期刊：
Trends in genetics : TIG
影响因子：
--
作者：
Davis JK;Broadie K
通讯作者：
Broadie K
DOI：
10.1177/1755738020958183
发表时间：
1995-02
期刊：
InnovAiT
影响因子：
--
作者：
Rebecca Dunphy
通讯作者：
Rebecca Dunphy
影响因子：
2
作者：
R. Dmochowski
通讯作者：
R. Dmochowski
影响因子：
16.6
作者：
Sethna F;Feng W;Ding Q;Robison AJ;Feng Y;Wang H
通讯作者：
Wang H