Fragile mental retardation protein interacts with the RNA-binding protein Caprin1 in neuronal RiboNucleoProtein complexes

Fragile X syndrome is caused by the absence of the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein. FMRP is associated with messenger RiboNucleoParticles (mRNPs) present in polyribosomes and its absence in neurons leads to alteration in synaptic plasticity as a result of translation regulation defects. The molecular mechanisms by which FMRP plays a role in translation regulation remain elusive. Using immunoprecipitation approaches with monoclonal Ab7G1-1 and a new generation of chicken antibodies, we identified Caprin1 as a novel FMRP-cellular partner. In vivo and in vitro evidence show that Caprin1 interacts with FMRP at the level of the translation machinery as well as in trafficking neuronal granules. As an RNA-binding protein, Caprin1 has in common with FMRP at least two RNA targets that have been identified as CaMKIIα and Map1b mRNAs. In view of the new concept that FMRP species bind to RNA regardless of known structural motifs, we propose that protein interactors might modulate FMRP functions.     

From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome

The mental retardation protein FMRP is involved in the transport of mRNAs and their translation at synapses. Patients with fragile X syndrome, in whom FMRP is absent or mutated, show deficits in learning and memory that might reflect impairments in the translational regulation of a subset of neuronal mRNAs. The study of FMRP provides important insights into the regulation and functions of local protein synthesis in the neuronal periphery, and increases our understanding of how these functions can produce specific effects at individual synapses.     

Fragile X mental retardation protein (FMRP) binds specifically to the brain cytoplasmic RNAs BC1/BC200 via a novel RNA-binding motif

Fragile X mental retardation protein (FMRP), the protein responsible for the fragile X syndrome, is an RNA-binding protein involved in localization and translation of neuronal mRNAs. One of the RNAs known to interact with FMRP is the dendritic non-translatable brain cytoplasmic RNA 1 BC1 RNA that works as an adaptor molecule linking FMRP and some of its regulated mRNAs. Here, we showed that the N terminus of FMRP binds strongly and specifically to BC1 and to its potential human analog BC200. This region does not contain a motif known to specifically recognize RNA and thus constitutes a new RNA-binding motif. We further demonstrated that FMRP recognition involves the 5' stem loop of BC1 and that this is the region that exhibits complementarity to FMRP target mRNAs, raising the possibility that FMRP plays a direct role in BC1/mRNA annealing.     

Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function.

Loss of fragile X mental retardation protein (FMRP) function causes the fragile X mental retardation syndrome. FMRP harbors three RNA binding domains, associates with polysomes, and is thought to regulate mRNA translation and/or localization, but the RNAs to which it binds are unknown. We have used RNA selection to demonstrate that the FMRP RGG box binds intramolecular G quartets. This data allowed us to identify mRNAs encoding proteins involved in synaptic or developmental neurobiology that harbor FMRP binding elements. The majority of these mRNAs have an altered polysome association in fragile X patient cells. These data demonstrate that G quartets serve as physiologically relevant targets for FMRP and identify mRNAs whose dysregulation may underlie human mental retardation.     

Advances in understanding of fragile X pathogenesis and FMRP function,and in identification of X linked mental retardation genes

The fragile X mental retardation syndrome is caused by large methylated expansions of a CGG repeat in the FMR1 gene that lead to the loss of expression of FMRP, an RNA-binding protein. FMRP is proposed to act as a regulator of mRNA transport or translation that plays a role in synaptic maturation and function. The recent observations of unexpected phenotypes in some carriers of fragile X premutations suggest a pathological role, in these individuals, of an abnormal FMR1 mRNA. FMRP was recently shown to interact preferentially with mRNAs containing a G quartet structure. Mouse and Drosophila models are used to decipher the function of FMRP, which was found to inhibit translation of some mRNA targets, but may be stimulatory in other cases. Proteins interacting with FMRP have been identified, and suggest a link with the Rac1 GTPase pathway that is important in neuronal maturation. Recent advances also include identification of other genes implicated in X-linked mental retardation.     

The fragile X mental retardation protein interacts with a distinct mRNA nuclear export factor NXF2

Loss of fragile X mental retardation protein, FMRP, causes the fragile X syndrome. Highly expressed in the brain and testis, FMRP has been implicated in the transport and translation of specific mRNAs. Here we show that FMRP and the mRNA nuclear export factor NXF2 co-express in the mouse male germ cells and hippocampal neurons and that FMRP associates with NXF2 but not with its close relative NXF1. We thus hypothesize that FMRP and NXF2 may act in concert to promote the nucleocytoplasmic transport of specific mRNAs in male germ cells and neurons.     

microRNA在脆性X综合征发病机制中的研究进展

脆性X综合征(fragile X syndrome,FXS)是最常见的遗传性认知障碍疾病,也是一种与自闭症谱系障碍(autism spectrum disorder,ASD)相关的严重的基因疾病.它主要是由于脆性X智力低下基因1(fragile X mental retardation 1,FMR1)的异常扩增及其上游Cp G岛的异常甲基化,导致其编码的脆性X智力低下蛋白(fragile X mental retardation protein,FMRP)表达减少或缺失引起的.FMRP与miRNA(micro RNA)均具有翻译抑制活性,而且FMRP在生物化学和遗传学上均与miRNA调控通路有相互作用.此外,越来越多的研究发现miRNA调控通路在FXS的发病和治疗中发挥作用.因此,本文对miRNA的功能及其与脆性X蛋白家族成员间的相互作用进行阐述,为在miRNA水平了解FXS的发病机制奠定基础.     

Fragile X Mental Retardation Protein Regulates Proliferation and Differentiation of Adult Neural Stem/Progenitor Cells

Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by the loss of functional fragile X mental retardation protein (FMRP). FMRP is an RNA–binding protein that can regulate the translation of specific mRNAs. Adult neurogenesis, a process considered important for neuroplasticity and memory, is regulated at multiple molecular levels. In this study, we investigated whether Fmrp deficiency affects adult neurogenesis. We show that in a mouse model of fragile X syndrome, adult neurogenesis is indeed altered. The loss of Fmrp increases the proliferation and alters the fate specification of adult neural progenitor/stem cells (aNPCs). We demonstrate that Fmrp regulates the protein expression of several components critical for aNPC function, including CDK4 and GSK3β. Dysregulation of GSK3β led to reduced Wnt signaling pathway activity, which altered the expression of neurogenin1 and the fate specification of aNPCs. These data unveil a novel regulatory role for Fmrp and translational regulation in adult neurogenesis.     

Regulation of RNA granules by FMRP and implications for neurological diseases

RNA granule formation, which can be regulated by RNA‐binding proteins (RBPs) such as fragile X mental retardation protein (FMRP), acts as a mechanism to control both the repression and subcellular localization of translation. Dysregulated assembly of RNA granules has been implicated in multiple neurological disorders, such as amyotrophic lateral sclerosis. Thus, it is crucial to understand the cellular pathways impinging upon granule assembly or disassembly. The goal of this review is to summarize recent advances in our understanding of the role of the RBP, FMRP, in translational repression underlying RNA granule dynamics, mRNA transport and localized. We summarize the known mechanisms of translational regulation by FMRP, the role of FMRP in RNA transport granules, fragile X granules and stress granules. Focusing on the emerging link between FMRP and stress granules, we propose a model for how hyperassembly and hypoassembly of RNA granules may contribute to neurological diseases.     

Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression

Genetic deletion of fragile X mental retardation protein (FMRP) has been shown to enhance mGluR-dependent long-term depression (LTD). Herein, we demonstrate that mGluR-LTD induces a transient, translation-dependent increase in FMRP that is rapidly degraded by the ubiquitin-proteasome pathway. Moreover, proteasome inhibitors abolished mGluR-LTD, and LTD was absent in mice that overexpress human FMRP. Neither translation nor proteasome inhibitors blocked the augmentation of mGluR-LTD in FMRP-deficient mice. In addition, mGluR-LTD is associated with rapid increases in the protein levels of FMRP target mRNAs in wild-type mice. Interestingly, the basal levels of these proteins were elevated and their synthesis was improperly regulated during mGluR-LTD in FMRP-deficient mice. Our findings indicate that hippocampal mGluR-LTD requires the rapid synthesis and degradation of FMRP and that mGluR-LTD triggers the synthesis of FMRP binding mRNAs. These findings indicate that the translation, ubiquitination, and proteolysis of FMRP functions as a dynamic regulatory system for controlling synaptic plasticity.     

Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function

Fragile X syndrome is the most common inherited form of cognitive deficiency in humans and perhaps the best-understood single cause of autism. A trinucleotide repeat expansion, inactivating the X-linked FMR1 gene, leads to the absence of the fragile X mental retardation protein. FMRP is a selective RNA-binding protein that regulates the local translation of a subset of mRNAs at synapses in response to activation of Gp1 metabotropic glutamate receptors (mGluRs) and possibly other receptors. In the absence of FMRP, excess and dysregulated mRNA translation leads to altered synaptic function and loss of protein synthesis-dependent plasticity. Recent evidence indicates the role of FMRP in regulated mRNA transport in dendrites. New studies also suggest a possible local function of FMRP in axons that may be important for guidance, synaptic development, and formation of neural circuits. The understanding of FMRP function at synapses has led to rationale therapeutic approaches.     

BC1-FMRP interaction is modulated by 2'-O-methylation: RNA-binding activity of the tudor domain and translational regulation at synapses

The brain cytoplasmic RNA, BC1, is a small non-coding RNA that is found in different RNP particles, some of which are involved in translational control. One component of BC1-containing RNP complexes is the fragile X mental retardation protein (FMRP) that is implicated in translational repression. Peptide mapping and computational simulations show that the tudor domain of FMRP makes specific contacts to BC1 RNA. Endogenous BC1 RNA is 2'-O-methylated in nucleotides that contact the FMRP interface, and methylation can affect this interaction. In the cell body BC1 2'-O-methylations are present in both the nucleus and the cytoplasm, but they are virtually absent at synapses where the FMRP-BC1-mRNA complex exerts its function. These results strongly suggest that subcellular region-specific modifications of BC1 affect the binding to FMRP and the interaction with its mRNA targets. We finally show that BC1 RNA has an important role in translation of certain mRNAs associated to FMRP. All together these findings provide further insights into the translational regulation by the FMRP-BC1 complex at synapses.     

Evidence for the association of the human regulatory protein Ki-1/57 with the translational machinery

Ki-1/57 is a cytoplasmic and nuclear protein of 57 kDa first identified in malignant cells from Hodgkin's lymphoma. Based on yeast-two hybrid protein interaction we found out that Ki-1/57 interacts with adaptor protein RACK1 (receptor of activated kinase 1), CIRP (cold-inducible RNA-binding protein), RPL38 (ribosomal protein L38) and FXR1 (fragile X mental retardation-related protein 1). Since these proteins are involved in the regulation of translation we suspected that Ki-1/57 may have a role in it. We show by immunoprecipitation the association of Ki-1/57 with FMRP. Confocal microscopy revealed that Ki-1/57 colocalizes with FMRP/FXR1/2 to stress granules. Furthermore Ki-1/57 cosediments with free ribosomal particles and enhances translation, when tethered to a reporter mRNA, suggesting that Ki-1/57 may be involved in translational regulation.     

Mechanisms of translational regulation in Drosophila

Translational regulation plays an essential role in many phases of the Drosophila life cycle. During embryogenesis, specification of the developing body pattern requires co-ordination of the translation of oskar, gurken and nanos mRNAs with their subcellular localization. In addition, dosage compensation is controlled by Sex-lethal-mediated translational regulation while dFMR1 (the Drosophila homologue of the fragile X mental retardation protein) controls translation of various mRNAs which function in the nervous system. Here we describe some of the mechanisms that are utilized to regulate these various processes. Our review highlights the complexity that can be involved with multiple factors employing different mechanisms to control the translation of a single mRNA.