Transcription, translation and fragile X syndrome
Kathryn Garber1, Karen T Smith2, Danny Reines2 and Stephen T Warren1,2
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.
Addresses
1
Department of Human Genetics, 615 Michael Street, Room 300,
Emory University, Atlanta, GA 30322, USA
2
Department of Biochemistry, 4023 Rollins Research Center,
Emory University, Atlanta, GA 30322, USA
Corresponding author: Warren, Stephen T
([email protected])
Current Opinion in Genetics & Development 2006, 16:270–275
This review comes from a themed issue on
Genetics of disease
Edited by Andrea Ballabio, David Nelson and Steve Rozen
Available online 2nd May 2006
0959-437X/$ – see front matter
# 2006 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.gde.2006.04.010
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 50 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
Current Opinion in Genetics & Development 2006, 16:270–275
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 overactivity 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 [10–12]. FMRP recognizes two threedimensional 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
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Transcription, translation and fragile X syndrome Garber, Smith, Reines and Warren 271
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.
F M R1 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
RNase III enzyme Dicer [17]. This suggests a possible
scenario whereby transient expression of the fully mutant
FMR1 in the developing embryo results in microRNAlike CGG fragments that, in turn, recruit chromatin
modification activities back to the FMR1 locus [18].
Indeed, commensurate with the shut down of the FMR1
full mutation is loss of acetylation of histone H3 and H4, a
reduction in methylation of H3 (lysine 4), and a large
increase in methylation of H3 (lysine 9) [19,20]. Acetylation of H3 is more tightly associated with FMR1 transcriptional activity than is acetylation of H4; the latter is
clearly insufficient for transcription or an open chromatin
configuration of FMR1 [19,20]. Pharmacological
demethylation of FMR1 DNA results in a reversal of
the histone modifications and a resumption of transcription [20,21]. Whether DNA methylation and histone
methylation are directly linked, however, is an important,
unresolved mechanistic question.
The change in the FMR1 local environment from transcriptionally active chromatin to inactive heterochromatin
correlates with the loss of four in vivo footprints normally
found on the active FMR1 promoter [22,23]. The four
occupied sites in the promoter include a palindrome, two
GC-like boxes, and an overlapping E-box–CRE (cAMP
response element) site. Identification of the proteins
residing at these sites, and their roles in FMR1 transcription have been addressed in several studies [22–
27,28 ,29,30]. Perhaps the two most important factors
are nuclear respiratory factor 1 (NRF1) and Sp1. NRF1
specifically binds to the GC-rich palindrome in vitro and
in vivo and is a strong activator of FMR1 transcription
[27,28 ]. The functionally related nuclear respiratory
factor 2 (NRF2) also controls FMR1 expression [30].
NRF1 and NRF2 are best known for regulating transcription of nuclear genes involved in mitochondrial function
[31]. However, recognition sites for both of these factors
are also present in promoters of several genes encoding
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proteins that bind RNA or are associated with translation,
including FMR1, eIF2-a, eIF2-b and hnRNP-A2
[22,30,32]. Therefore, FMR1 might fit into a potential
NRF1- and NRF2-controlled regulon of RNA metabolism-related genes. This may be of particular importance
in the brain, because NRF1 and NRF2 have suspected
roles in neuronal function, and the tight control of translation is especially crucial in neurons [33–35].
Sp1 can bind to and activate 100-fold increased levels of
FMR1 transcription from two recognition sites in the
promoter, both in vitro and in vivo [24,26,28 ]. Sp1 activity
is the strongest of the factors involved in FMR1 transcription and is the most resistant to DNA methylation [28 ].
Given that Sp1 can still activate transcription in the
presence of DNA methylation, but that its binding is lost
at the fragile X allele, complete silencing of FMR1
undoubtedly requires an additional event [20,28 ]. The
presence of the methyl-CpG-binding protein, MeCP2,
and the chromatin-remodeling protein Brahma might be
one of the factors preventing Sp1’s occupancy on the
FMR1 promoter in fragile X patient cells [36 ].
The identity of the transcription factor binding the overlapping E-box and CRE has raised some controversy
[25,27]. In vivo studies reveal that both USF (upstream
stimulatory factor) and CREB bind to the FMR1 promoter
region; however, only CREB acts positively though the Ebox–CRE site [28 ,30]. Regulation of CREB transcriptional activity through cAMP has been well studied in
brain, particularly in regards to learning and memory [37].
Early work showed that a transfected FMR1-driven reporter could be activated by a cAMP agonist [25]. However,
using the PC12 model system, Smith et al. [30] were
unable to show induction of endogenous FMR1 in
response to cAMP agonists under conditions in which
c-fos was responsive.
These results suggest that transcriptional induction of
FMR1 does not normally appear to regulate synaptic
functioning in adult neurons in culture, at least not in
response to cAMP or depolarization [30]. However, inducible regulation of FMR1 transcription during development can not be excluded. In fact, a role for AP2 in
controlling FMR1 expression during development has
been suggested, but the signals that might stimulate
FMR1 developmentally are unknown [29].
It may be that FMR1 does not need to be induced at the
transcriptional level in adult neurons, because post-transcriptional events for FMR1 are responsive to certain
stimuli. Treatment of primary neurons with KCl rapidly
induces localization of both FMR1 mRNA and FMRP to
dendrites [38]. In addition, FMRP is quickly translated
within five minutes of glutamate receptor stimulation of
neurons [39]. These stimulations can also activate CREB;
however, it would take longer to make FMRP through a
Current Opinion in Genetics & Development 2006, 16:270–275
272 Genetics of disease
transcriptional induction pathway than to directly
increase FMRP levels by post-transcriptional processes
[40]. Hence, mobilization of pre-existing FMR1 mRNA
and protein, along with rapid local translation, may be
more important for the neuronal function of FMRP than
new FMR1 mRNA synthesis. In support of this hypothesis, FMRP levels increase in cortical neurons following
stimulation by light exposure, but mRNA levels do not
[41]. FMR1 mRNA may be produced in sufficient
amounts on a continuous basis, supporting the dynamic
control of FMRP expression in adults at or near the
synapse through post-transcriptional processes. For this
predominantly cytoplasmic protein, the time saved by not
having to signal to the nucleus could be crucial for its
neuronal function
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 rapidly
translated at the synapse in response to stimulation by
metabotropic glutamate receptors (mGluRs) — and
which may, therefore, have a role in LTP and LTD —
include FMR1 [38,45]. Supporting a role for FMRP in
LTD is the fact that LTD triggered by mGluRs is
selectively enhanced in mice that do not express Fmrp
[46,47]. Together with the evidence for FMRP’s role in
suppression of protein translation, these findings led to
the proposal that FMRP suppresses mGluR-stimulated
local protein synthesis at the dendrites, and that mGluRstimulated processes are exaggerated in fragile X syndrome [16]. This model is supported by the fact that
treatment with mGluR antagonists rescues behavioral
and neurological defects in Drosophila strains lacking
the FMR1 homolog dfmr1, as well as in mice that have
a disruption in Fmr1 [48,49].
It has also been argued that mGluR-stimulated bursts
of protein synthesis require FMRP [45,50]. In these
experiments, stimulation of polyribosome assembly in
synaptoneurosome preparations, or of protein synthesis
in cortical cultures, was observed for wild type mice
but not for Fmr1 knockouts. These results were used
to argue that, in addition to its role in suppressing
mGluR-stimulated protein translation, FMRP also plays
a positive role in protein translation under certain circumstances, and that perhaps the role that FMRP takes is
spatially dictated [51]. Recent reports that FMRP is
associated with actively translating polyribosomes in
neurons support a role for FMRP in promoting translation [52,53].
Current Opinion in Genetics & Development 2006, 16:270–275
More recent data suggest that, perhaps in the absence of
FMRP, protein synthesis is not stimulated by mGluR,
because protein synthesis is already enhanced to a maximal level and cannot be further stimulated through the
receptor [54 ]. If this is the case, then prior accumulation
of the proteins whose production would normally be
stimulated by mGluR could circumvent the requirement
for protein synthesis in mGluR-mediated LTD. Indeed,
this is true in Fmr1 knockout mice; unlike in wild type
mice, the presence of translation inhibitors in these mice
does not prevent mGluR-mediated LTD [54 ]. Protein
synthesis-independent LTD in Fmr1 knockout mice is
not generated through an alternative pathway, because, as
in wild type mice, mGluR-stimulated LTD is associated
with decreases in cell surface expression of AMPA receptors, and this decrease in receptors also loses its protein
synthesis-dependence in Fmr1 knockout mice [54 ]. Production of a different set of proteins or the use of a
different pathway may be involved in other aspect of
fragile X syndrome pathogenesis, however, because
mGluR-stimulated protein synthesis is still required for
the enhanced epileptiform bursts that are seen in hippocampal slices from Fmr1 knockout mice [55]. The development of prolonged epileptiform discharges in the
mutant mice is blocked by treatment with ERK1 and/
or ERK2 (extracellular signal-regulated kinases) inhibitors, implicating ERK-containing signal transduction
pathways in this process [55].
One factor as yet unknown is the mechanism by which
FMRP activity is regulated. FMRP phosphorylation suppresses translation in FMRP-associated polyribosomes
[56]. mGluR5 stimulation is known to decrease the activity of the phosphatase PP2A [57]. One could speculate
that PP2A is the phosphatase that acts on FMRP to
release its translation-suppressing effect. The fact that
FMRP binds to pp2acb mRNA and represses its translation [58] suggests an interesting regulatory loop whereby
FMRP could control its own activity by modulating levels
of its activating phosphatase.
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 basepairing 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 was shown to be crucial for the
effects of dfmr1 on synaptic plasticity [15 ].
New reports provide further detail on the regulation of
synaptic protein synthesis by RISC and FMRP. This
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Transcription, translation and fragile X syndrome Garber, Smith, Reines and Warren 273
regulation includes an mRNA transport component and a
translational silencing component, as was shown for the
synthesis of the calcium–calmodulin-dependent kinase II
(CaMKII), a protein required for memory formation
[61 ]. Upon neural stimulation, CaMKII mRNA is transported to the dendrites in a process that requires protein
synthesis and sequences in the 30 UTR of CaMKII.
Within this 30 UTR are predicted binding sites for the
miRNAs miR-280 and miR-289. RISC inhibits translation
of the CaMKII message, and this inhibition is relieved
upon neural stimulation, at which time components of
RISC, such as Armitage, are degraded by the proteasome.
Armitage further controls expression of Staufen and the
kinesin heavy chain (Khc), which, along with the CaMKII
mRNA and FMRP, are found in RNA transport granules
[62].
Further support for the role of miRNAs in dendritic spine
development comes through the finding that miR-134
inhibits translation of Lim-domain-containing protein
kinase 1 (LimK1), which has a role in dendritic spine
structure [63 ]. Stimulation of rat hippocampal neurons
using brain-derived neurotrophic factor (BDNF) relieves
the inhibition of LimK1 translation, thereby promoting
dendritic spine growth. As in the previous experiments,
these authors also believe that the miRNA maintains
mRNAs in a translationally suppressed state during transport of the messages to the dendrites within granules.
Once there, they are ready to be translated in an activitydependent manner, as is required for synaptic plasticity.
FMRP is another factor that has a role in maintaining
translational suppression during RNA transport. The
level of granules in the brains of Fmr1 knockout mice
is reduced; although granules can form in the absence of
FMRP, their disassembly in response to mGluR stimulation is exaggerated [64]. Stimulation of mGluRs increases
the transport of FMRP-containing granules to the dendrites [65]. This stimulation also increases the level of
Fmr1 mRNA and reduces the level of FMRP at synapses,
perhaps reflecting the process of granule disassembly
[65].
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 the dendrites as granules. Stimulation of
neurons increases the transport of messages to the dendrites and it also activates the proteasome to degrade
RISC, thus enabling rapid translation of the messages that
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were contained therein. The disassembly of granules in
response to mGluR stimulation could perhaps reflect the
degradation of RISC components, whereas the reduction
of FMRP at the synapse could reflect the recycling of
some granule components back to the cell body for
further use. In the absence of FMRP, the cell lacks
the opposing effect to mGluR stimulation, and this leads
to increased levels of the proteins normally stimulated by
this system. These increased protein levels result in the
abnormal dendritic spine morphology observed in people
and animal models that lack FMRP.
Conclusions
We now understand in detail the consequence of repeatmediated 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 orchestrated protein synthesis that can occur immediately upon
stimulation of a synapse. It is becoming clear that FMRP
is a crucial component of this process and is involved in
the transport of the appropriate messages to the synapse
and in holding them in their silent state until the precise
time that they are needed. As is abundantly clear from
individuals with fragile X syndrome, the lack of this
protein has severe ramifications for the development
and function of the brain.
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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