Multifarious Functions of the Fragile X Mental Retardation Protein

doi:10.1016/j.tig.2017.07.008

Trends in Genetics

Volume 33, Issue 10, October 2017, Pages 703-714

https://doi.org/10.1016/j.tig.2017.07.008 Get rights and content

Trends

FXS, a leading heritable autism, is caused by a 5′ untranslated region (UTR) trinucleotide repeat expansion in the gene encoding FMRP.

The disease presents with stereotypical hyperexcitability and synaptic overelaboration, which are well replicated across a range of neural circuits in genetic models.

Canonically, FMRP is a mRNA-binding translational suppressor, but genetic roles range from chromatin binding to mRNA splicing and/or editing to other forms of translation control.

Additional FMRP roles include direct ion channel binding to regulate neural excitability, which may be an independent function or linked to activity-dependent translation control.

FXS cell type-specific defects in neurons and glia include altered calcium signaling, critical period synapse refinement, and E/I imbalance in neural circuitry.

Fragile X syndrome (FXS), a heritable intellectual and autism spectrum disorder (ASD), results from the loss of Fragile X mental retardation protein (FMRP). This neurodevelopmental disease state exhibits neural circuit hyperconnectivity and hyperexcitability. Canonically, FMRP functions as an mRNA-binding translation suppressor, but recent findings have enormously expanded its proposed roles. Although connections between burgeoning FMRP functions remain unknown, recent advances have extended understanding of its involvement in RNA, channel, and protein binding that modulate calcium signaling, activity-dependent critical period development, and the excitation–inhibition (E/I) neural circuitry balance. In this review, we contextualize 3 years of FXS model research. Future directions extrapolated from recent advances focus on discovering links between FMRP roles to determine whether FMRP has a multitude of unrelated functions or whether combinatorial mechanisms can explain its multifaceted existence.

Section snippets

Overview of Expanding FMRP Functions

FXS (see Glossary), a common genetic root of both intellectual disorders and ASD, is usually caused by a 5′ untranslated region (UTR) trinucleotide repeat expansion in the FMR1 gene, resulting in loss of FMRP. FMRP functions as a master regulator of activity-dependent neurodevelopment, with null mutants manifesting hyperexcitability and reduced activity-dependent modulation of synapse maturation, refinement, and plasticity [1]. FMRP is canonically defined as an mRNA-binding translational

New Progress in RNA-Binding/Translation Suppression Mechanisms

The canonical FMRP role is direct mRNA-binding translation suppression (Figure 1), although FMRP has long been associated with mRNA throughout its lifecycle, including splicing, editing, trafficking, and stability 6, 11, 12, 29, 30. FMRP selectively associates with a subset of mRNAs: the candidate target list is long, but altered protein levels have been established for only a few proteins (Table 2) 29, 31. Indeed, proteomic screens suggest that the number of protein changes in both mouse and

New Progress in Channel-Binding and Calcium-Signaling Mechanisms

In addition to translation roles, FMRP directly binds ion channels (Figure 1), and modulates Ca²⁺ signaling to control neural activity [1]. FMRP binds multiple classes of K⁺ channel, including Na⁺-activated Slack [16] and Ca²⁺-activated Slowpoke (Slo) BK channels [17]. FMRP-Slack binding regulates gating to shape action potential kinetics, especially during high-frequency activity. FMRP binding to presynaptic BK channels modulates Ca²⁺ influx and neurotransmitter release (Figure 1). In addition

New Progress in Activity-Dependent Synapse Development Mechanisms

The critical question of FMRP roles during neurodevelopment versus maturity is centrally important for determining optimal FXS treatment strategies 1, 2, 21, 25, 26. Recent FXS clinical trials have been greatly disappointing, but this may be in large part due to targeting adult patients [21]. Moreover, many mouse FXS model interpretations may be complicated by ‘adult’ studies initiated in animals at approximately 4 weeks of age, which overlaps the neurodevelopmental period [61]. In the

New Progress in Excitatory/Inhibitory Balance Mechanisms

The metabotropic glutamate receptor (mGluR) theory of FXS hyperexcitability 68, 69 is developmentally restricted, with early defects later corrected 22, 24. In mice, FMRP loss causes mGluR type 1 and/or 5 (mGluR1/5) pathway activation. In the Drosophila FXS model, elevated phosphatidylinositide 3-kinase enhancer (PIKE) levels exaggerate mGluR1/5 signaling to both impair synaptic plasticity and cause hyperexcitability [70]. One result of this mGluR hyperexcitability is the well-documented

Concluding Remarks and Future Directions

Canonically, FMRP is an mRNA-binding translational suppressor. However, at a foundational level, we still do not fully understand the binding mechanism to specific mRNA targets. This question is complicated by our ever-increasing grasp of mRNA complexity 11, 12, as well as by examples of FMRP acting as a translational activator [55]. FMRP also has multiple mRNA-binding domains [35], but it is not clear whether they work together, separately, or sequentially. Moreover, FMRP interacts with

Acknowledgments

We thank Caleb Doll for help with Figure 1. We are grateful to Dominic Vita, Jim Sears, Randy Golovin, and Tyler Kennedy for critical input on this article. This work is supported by R01 MH084989 to K.B.

Glossary

Activity-regulated cytoskeleton-associated protein (ARC): an immediate-early gene (IEG) displaying activity-dependent mRNA localization to the synapse, where local translation is involved in synaptic plasticity, learning and memory.
Adenosine deaminase acting on RNA (ADAR): a class of RNA-editing enzymes that bind double-stranded RNA to convert adenosine to inosine by direct deamination.
Adenylyl cyclase (ADCY1): converts ATP into the second messenger cAMP.
Amyloid precursor protein (APP): an integral

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Trends in Genetics

ReviewMultifarious Functions of the Fragile X Mental Retardation Protein

Trends

Section snippets

Overview of Expanding FMRP Functions

New Progress in RNA-Binding/Translation Suppression Mechanisms

New Progress in Channel-Binding and Calcium-Signaling Mechanisms

New Progress in Activity-Dependent Synapse Development Mechanisms

New Progress in Excitatory/Inhibitory Balance Mechanisms

Concluding Remarks and Future Directions

Acknowledgments

Glossary

Neurobiol. Dis.

Exp. Neurol.

Cell

Neuroscience

Neuron

Neurobiol. Dis.

Mol. Cell

Neuron

J. Biol. Chem.

Biochimie

Neuroscience

Neuron

Neurobiol. Dis.

Cell Rep.

Neuron

Curr. Biol.

A novel Fragile X syndrome mutation reveals a conserved role for the carboxy-terminus in FMRP localization and function

EMBO Mol. Med.

A feed-forward mechanism involving Drosophila Fragile X mental retardation protein triggers a replication stress-induced DNA damage response

Hum. Mol. Genet.

FMRP interacts with Adar and regulates RNA editing, synaptic density and locomotor activity in zebrafish

PLoS Genet.

Absence of the Fragile X mental retardation protein results in defects of RNA editing of neuronal mRNAs in mouse

RNA Biol.

Developmental experience-dependent plasticity in the first synapse of the Drosophila olfactory circuit

J. Neurophysiol.

FMRP and Ataxin-2 function together in long-term olfactory habituation and neuronal translational control

PNAS

RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation

Genes Dev.

Post-transcriptional gene regulation by mRNA modifications

Nat. Rev. Mol. Cell Biol.

The FMR1 promoter is selectively hydroxymethylated in primary neurons of Fragile X syndrome patients

Hum. Mol. Genet.

Depletion of the Fragile X mental retardation protein in embryonic stem cells alters the kinetics of neurogenesis

Stem Cells

Astrocytic contributions to synaptic and learning abnormalities in a mouse model of Fragile X syndrome

Biol. Psychiatry

Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack

Nat. Neurosci.

Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density

Nat. Commun.

Deficits in the activity of presynaptic γ-aminobutyric acid type B receptors contribute to altered neuronal excitability in Fragile X syndrome

J. Biol. Chem.

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

PNAS

Molecular medicine of Fragile X syndrome: based on known molecular mechanisms

World J. Pediatr.

Differential adulthood onset mGlu5 signaling saves prefrontal function in the Fragile X mouse

Cereb. Cortex

Altered connectivity and synapse maturation of the hippocampal mossy fiber pathway in a mouse model of the Fragile X syndrome

Cereb. Cortex

Sensory hypo-excitability in a rat model of fetal development in Fragile X syndrome

Sci. Rep.

Activity-dependent FMRP requirements in development of the neural circuitry of learning and memory

Development

Impaired activity-dependent neural circuit assembly and refinement in autism spectrum disorder genetic models

Front. Cell. Neurosci.

Review
Multifarious Functions of the Fragile X Mental Retardation Protein

RNA N⁶-methyladenosine methylation in post-transcriptional gene expression regulation