Fragile X mental retardation protein regulates trans-synaptic signaling in Drosophila.
Fragile X mental retardation protein regulates trans-synaptic signaling in Drosophila.
复制标题
DOI：
10.1242/dmm.012229
复制
发表时间：
2013-11
影响因子：
4.3
通讯作者：
Broadie K
中科院分区：
文献类型：
--
作者：
Friedman SH;Dani N;Rushton E;Broadie K
脆性X综合征（FXS）是智力残疾和自闭症谱系障碍最常见的遗传决定因素，是由脆性X智力发育迟滞1 （FMR1）基因产物（FMRP）缺失引起的，FMRP是一种mrna结合翻译抑制因子。在果蝇FXS疾病模型中已经发现了许多保守的FMRP靶点，但FMRP在功能上是高度多效的，FMRP靶点的全谱尚未被揭示。在这项研究中，对果蝇fmr1 （dfmr1）零突变体中上调的神经蛋白的筛选显示，两种突触硫酸肝素蛋白聚糖（HSPGs）强烈升高：gpi锚定的glypican Dally-like protein （Dlp）和跨膜Syndecan （Sdc）。我们最近的工作表明，Dlp和Sdc作为共受体，在驱动突触发生的多种跨突触通路中调节细胞内信号转导上游的细胞外配体。与之一致的是，dfmr1空突触表现出WNT信号的改变，其变化包括无翼（Wg）配体丰度和下游卷曲-2 （Fz2）受体c端核输入。类似地，平行的顺行信号配体Jelly belly （Jeb）和下游ERK磷酸化（dpERK）在dfmr1空突触被抑制。相反，逆行BMP配体玻璃底船（Gbb）和通过转录因子MAD （pMAD）磷酸化的下游信号传导似乎不受影响。为了确定HSPG上调是否会导致突触性缺陷，我们在dfmr1缺失背景下将HSPG基因降低到控制水平。HSPG校正恢复了(1)Wg和Jeb突触传递信号，(2)突触结构和传递强度恢复到野生型水平。综上所述，这些数据表明FMRP在突触发生过程中负调控控制突触转信号的HSPG共受体，这种调控的缺失导致表征FXS疾病状态的突触结构和功能缺陷。
Fragile X syndrome (FXS), the most common inherited determinant of intellectual disability and autism spectrum disorders, is caused by loss of the fragile X mental retardation 1 (FMR1) gene product (FMRP), an mRNA-binding translational repressor. A number of conserved FMRP targets have been identified in the well-characterized Drosophila FXS disease model, but FMRP is highly pleiotropic in function and the full spectrum of FMRP targets has yet to be revealed. In this study, screens for upregulated neural proteins in Drosophila fmr1 (dfmr1) null mutants reveal strong elevation of two synaptic heparan sulfate proteoglycans (HSPGs): GPI-anchored glypican Dally-like protein (Dlp) and transmembrane Syndecan (Sdc). Our recent work has shown that Dlp and Sdc act as co-receptors regulating extracellular ligands upstream of intracellular signal transduction in multiple trans-synaptic pathways that drive synaptogenesis. Consistently, dfmr1 null synapses exhibit altered WNT signaling, with changes in both Wingless (Wg) ligand abundance and downstream Frizzled-2 (Fz2) receptor C-terminal nuclear import. Similarly, a parallel anterograde signaling ligand, Jelly belly (Jeb), and downstream ERK phosphorylation (dpERK) are depressed at dfmr1 null synapses. In contrast, the retrograde BMP ligand Glass bottom boat (Gbb) and downstream signaling via phosphorylation of the transcription factor MAD (pMAD) seem not to be affected. To determine whether HSPG upregulation is causative for synaptogenic defects, HSPGs were genetically reduced to control levels in the dfmr1 null background. HSPG correction restored both (1) Wg and Jeb trans-synaptic signaling, and (2) synaptic architecture and transmission strength back to wild-type levels. Taken together, these data suggest that FMRP negatively regulates HSPG co-receptors controlling trans-synaptic signaling during synaptogenesis, and that loss of this regulation causes synaptic structure and function defects characterizing the FXS disease state.
登录
查看更多内容
影响因子：
3
作者：
Broadie, Kendal;Baumgartner, Stefan;Prokop, Andreas
通讯作者：
Prokop, Andreas
影响因子：
16.2
作者：
Dockendorff, TC;Su, HS;Jongens, TA
通讯作者：
Jongens, TA
影响因子：
5.7
作者：
Budnik V;Salinas PC
通讯作者：
Salinas PC
DOI：
10.1002/ajmg.1320410306
发表时间：
1991-12-01
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
HINTON, VJ;BROWN, WT;RUDELLI, RD
通讯作者：
RUDELLI, RD
影响因子：
7.2
作者：
Barros, Claudia S.;Franco, Santos J.;Mueller, Ulrich
通讯作者：
Mueller, Ulrich