Transcription, translation and fragile X syndrome

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The fragile X mental retardation protein (FMRP) plays a role in the control of local protein synthesis in the dendrites. Loss of its production in fragile X syndrome is associated with transcriptional dysregulation of the gene. Recent work demonstrates that Sp1 and NRF1 transcriptionally control this gene. Other studies reveal how the microRNA pathway and signaling are related to FMRP function through the metabotropic glutamate receptor. These studies provide new insights through which we can better understand the inactivation of the FMR1 gene and, in turn, the consequence of FMRP loss.

Introduction

The FMR1 (FRAGILE X MENTAL RETARDATION 1) gene is directly associated with three distinct diseases: fragile X syndrome, fragile X-associated tremor/ataxia syndrome, and premature ovarian failure [1, 2] (see also review by D Toniolo [3], this issue). All are caused by FMR1 alleles with expanded CGG trinucleotide repeats in the 5′ untranslated region. Although normal alleles contain, on average, 30 repeats, fragile X syndrome is caused by a massive expansion beyond 200 repeats (i.e. the full mutation), and both fragile X-associated tremor/ataxia syndrome and premature ovarian failure are associated with premutation alleles (i.e. 55–200 repeats). Both abnormal alleles result in transcriptional dysregulation of the FMR1 gene. Whereas fragile X syndrome is almost exclusively caused by a complete transcriptional shutdown of the gene, the premutation-associated diseases are caused by excess transcript levels leading to — at least for fragile X-associated tremor/ataxia syndrome — toxic effects of repeat-containing mRNA [1, 4, 5]. Given that mutations in FMR1 manifest two vastly different transcriptional defects, much work has gone into understanding the cis sequences and trans-acting proteins that normally influence this gene in addition to its chromatin structure.

Fragile X syndrome occurs in approximately 1 in 4000 males and in 1 in 8,000 females and presents as developmental delay around 36 months of age. Speech delay is frequent, along with behavior problems such as over-activity and anxiety. Many parallel phenotypes with autism are seen, such as gaze avoidance, stereotyped repetitive behavior, resistance to change in routines or environment, and preservation. Premutation males, and to a lesser degree females, can have fragile X-associated tremor ataxia syndrome with cerebellar tremor/ataxia, cognitive decline and generalized brain atrophy presenting beyond the fifth decade of life. Approximately 24% of premutation females also experience premature ovarian failure (i.e. cessation of menses at <40 years).

FMRP, the protein encoded by FMR1, is an RNA binding protein involved in the control of local protein synthesis. FMRP shuttles from the nucleus to the cytoplasm, where it associates with polyribosomes through large mRNP particles [6] and suppresses translation of a selective group of mRNAs to which it binds [7, 8]. In vivo, the lack of Fmrp in mice is associated with elevations in the rates of protein synthesis in certain regions of the brain [9]. Various approaches have been taken to identify the mRNAs associated with FMRP and its homologs, and these mRNAs include, among others, MAP1B (MICROTUBULE-ASSOCIATED PROTEIN 1B), the FMR1 message itself, and others involved in neuronal development and plasticity [10, 11, 12]. FMRP recognizes two three-dimensional structures in the RNAs: an intramolecular G-quartet and an intricate tertiary structure termed an FMRP-kissing complex [11, 13]. Interactions have also been discovered between FMRP and components of the microRNA pathway in addition to the microRNAs themselves, suggesting a mechanistic link in the regulation of protein synthesis [14, 15••]. Current theories suggest that FMRP is involved in the control of local translation within dendrites in response to synaptic activity, and that loss of FMRP results in defects in protein synthesis-dependent plasticity [16].

Two key aspects of FMR1 biology are in need of further mechanistic insight. One involves the FMR1 promoter and the process of transcriptional silencing in the full mutation and transcriptional enhancement in the premutation. The second is the precise function of FMRP in the neuron and the neuronal consequence of its loss in fragile X syndrome.

In this review, we focus on recent advances in our understanding of the transcription of the FMR1 gene and the influence of FMRP on translation.

Section snippets

FMR1 promoter function and chromatin structure

Loss of transcription of FMR1 in fragile X syndrome is the best understood of the FMR1-related disease processes. Repeat expansion results in cytosine methylation of the repeats in addition to the CpG island in the promoter. It appears that the full mutation-bearing FMR1 is recognized as repeated DNA and subjected to ‘heterochromatinization’, much as is transposon or centromeric DNA. Interestingly, it has been shown that long CGG-repeat tracts, as RNA, are substrates for the binding of the

FMRP and translational control

Synaptic transmission occurs at the dendritic spines, and in individuals with fragile X syndrome these spines are abnormally long and appear to be immature [42, 43]. This has led to the notion that FMRP is involved in synaptic maturation and spine-pruning. In the dendritic spines, long-term potentiation (LTP) and long-term depression (LTD) — two forms of synaptic plasticity — are triggered by synaptic activity through processes that require local protein synthesis [44]. The messages that are

FMRP and miRNAs work together to inhibit translation

MicroRNAs (miRNAs) are a class of non-coding RNAs that control translation of their target mRNAs by base-pairing with partially complementary transcript sequences [59]. miRNAs use the RNA-induced silencing complex (RISC) to effect their function. FMRP interacts with the Argonaute proteins AGO1 and AGO2, which are components of RISC, and with miRNAs [14, 15••, 60], so it has been proposed that the translational suppression associated with FMRP occurs through miRNAs. In support of this idea, AGO1

Current model of FMRP function

Synthesizing the current data on translational suppression by FMRP, we propose a model in which FMRP is transported into the nucleus, where it associates with specific RNA transcripts and forms messenger ribonucleoprotein complexes. These complexes are transported out of the nucleus, enabling them to interact with components of the RISC complex, thereby inhibiting the translation of the messages therein. Using kinesin as its motor, these translationally silent complexes can be transported to

Conclusions

We now understand in detail the consequence of repeat-mediated transcriptional shut-off of FMR1, and this knowledge, especially in comparison with transcriptional upregulation of premutation-sized repeats at this locus, will add to our basic understanding of gene regulation. Because this transcriptional shut-off causes fragile X syndrome through the loss of a single protein, it places FMRP in a central role for learning and memory. Synaptic plasticity requires tightly controlled and highly

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This research is supported by National Institutes of Health grants HD35576, HD20521 and HD24064. We apologize for work that could not be cited owing to space limitations.

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