New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes.
New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes.
复制标题
DOI：
10.1242/dmm.025809
复制
发表时间：
2017-04-01
影响因子：
4.3
通讯作者：
Bardoni B
中科院分区：
文献类型：
--
作者：
Abekhoukh S;Sahin HB;Grossi M;Zongaro S;Maurin T;Madrigal I;Kazue-Sugioka D;Raas-Rothschild A;Doulazmi M;Carrera P;Stachon A;Scherer S;Drula Do Nascimento MR;Trembleau A;Arroyo I;Szatmari P;Smith IM;Milà M;Smith AC;Giangrande A;Caillé I;Bardoni B
细胞质FMRP相互作用蛋白1（Cytoplasmic FMRP interacting protein 1，CYFIP 1）是智力残疾（intellectual disability，ID）、孤独症、精神分裂症和癫痫的候选基因。它是在进化过程中高度保守的蛋白质家族的成员，与果蝇同源物dCYFIP具有高度同源性。CYFIP 1与脆性X智力低下蛋白（FMRP，由FMR 1基因编码）相互作用，其缺失导致脆性X综合征，并与翻译起始因子eIF 4 E相互作用。它是WAVE调节复合物（WRC）的成员，因此代表了翻译调节和肌动蛋白细胞骨架之间的联系。在这里，我们目前的数据显示CYFIP 1和其他成员的WRC的mRNA水平之间的相关性。这表明WRC成员的水平的严格调节，而不仅仅是翻译后机制，如先前假设的。此外，我们研究了CYFIP 1和FMRP功能丧失对两种动物模型-苍蝇和小鼠-神经元生长和分化的影响。我们发现，这两种蛋白质相互拮抗的功能，不仅在神经肌肉接头生长的苍蝇，但也在新的神经元分化的成年小鼠的嗅球。从机制上讲，FMRP和CYFIP 1可能通过独立的途径以拮抗方式调节mTor信号传导，这支持了在小鼠和苍蝇中在形态学水平上获得的结果。总的来说，我们的研究结果说明了一个新的模型来解释FMRP和CYFIP 1的细胞作用及其相互作用的分子意义。总结：CYFIP 1和FMRP在果蝇神经肌肉接头生长过程中和成年小鼠嗅球中新神经元分化过程中相互拮抗。
Cytoplasmic FMRP interacting protein 1 (CYFIP1) is a candidate gene for intellectual disability (ID), autism, schizophrenia and epilepsy. It is a member of a family of proteins that is highly conserved during evolution, sharing high homology with its Drosophila homolog, dCYFIP. CYFIP1 interacts with the Fragile X mental retardation protein (FMRP, encoded by the FMR1 gene), whose absence causes Fragile X syndrome, and with the translation initiation factor eIF4E. It is a member of the WAVE regulatory complex (WRC), thus representing a link between translational regulation and the actin cytoskeleton. Here, we present data showing a correlation between mRNA levels of CYFIP1 and other members of the WRC. This suggests a tight regulation of the levels of the WRC members, not only by post-translational mechanisms, as previously hypothesized. Moreover, we studied the impact of loss of function of both CYFIP1 and FMRP on neuronal growth and differentiation in two animal models – fly and mouse. We show that these two proteins antagonize each other's function not only during neuromuscular junction growth in the fly but also during new neuronal differentiation in the olfactory bulb of adult mice. Mechanistically, FMRP and CYFIP1 modulate mTor signaling in an antagonistic manner, likely via independent pathways, supporting the results obtained in mouse as well as in fly at the morphological level. Collectively, our results illustrate a new model to explain the cellular roles of FMRP and CYFIP1 and the molecular significance of their interaction. Summary: CYFIP1 and FMRP interact antagonistically during neuromuscular junction growth in the fly and during new neuron differentiation in the olfactory bulb of the adult mouse.