Article thumbnail

Regulation of molecular pathways in the Fragile X Syndrome: insights into Autism Spectrum Disorders

By Silvia De Rubeis and Claudia Bagni

Abstract

The Fragile X syndrome (FXS) is a leading cause of intellectual disability (ID) and autism. The disease is caused by mutations or loss of the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein playing multiple functions in RNA metabolism. The expression of a large set of neuronal mRNAs is altered when FMRP is lost, thus causing defects in neuronal morphology and physiology. FMRP regulates mRNA stability, dendritic targeting, and protein synthesis. At synapses, FMRP represses protein synthesis by forming a complex with the Cytoplasmic FMRP Interacting Protein 1 (CYFIP1) and the cap-binding protein eIF4E. Here, we review the clinical, genetic, and molecular aspects of FXS with a special focus on the receptor signaling that regulates FMRP-dependent protein synthesis. We further discuss the FMRP–CYFIP1 complex and its potential relevance for ID and autism

Topics: Article
Publisher: Springer US
OAI identifier: oai:pubmedcentral.nih.gov:3167042
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles

Citations

  1. (2011). 3:257–269 265References Abrahams BS, Geschwind DH. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet.
  2. (1994). A deletion of 1.6 kb proximal to the CGG repeat of the FMR1 gene causes the clinical phenotype of the fragile X syndrome. Hum Mol Genet.
  3. (2008). A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome. Dev Cell.
  4. A genomewide screen of 345 families for autismsusceptibility loci.
  5. (2006). A heterogeneity-based genome search meta-analysis for autism-spectrum disorders. Mol Psychiatry.
  6. A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P .
  7. (1992). A microdeletion of less than 250 kb, including the proximal part of the FMR-I gene and the fragile-X site, in a male with the clinical phenotype of fragile-X syndrome.
  8. (2007). A new function for the fragile X mental retardation protein in regulation of PSD-95 mRNA stability. Nat Neurosci.
  9. (1993). A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nat Genet.
  10. (1996). A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity.
  11. (2004). A study of the distributional characteristics of FMR1 transcript levels in 238 individuals. Hum Genet.
  12. Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination.
  13. Abnormal striatal GABA transmission in the mouse model for the fragile X syndrome. Biol Psychiatry.
  14. (2010). Advances in understanding the molecular basis of FXTAS. Hum Mol Genet.
  15. (2010). Altered imprinting of the genes distally to the BP2 can give rise to three ASD-related syndromes, namely the 15q duplication syndrome, Angelman Syndrome, and PraderWilli Syndrome (Chamberlain and Lalande
  16. Altered mRNA transport, docking, and protein translation in neurons lacking fragile X mental retardation protein.
  17. Altered synaptic plasticity in a mouse model of fragile X mental retardation.
  18. (2001). and in
  19. (2005). Another view of the role of FMRP in translational regulation. Cell Mol Life Sci.
  20. Autism profiles of males with fragile X syndrome.
  21. (2009). Autism spectrum disorder in fragile X syndrome: a longitudinal evaluation.
  22. Autism spectrum disorders in genetic syndromes: implications for diagnosis, intervention and understanding the wider autism spectrum disorder population.
  23. (2007). Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol.
  24. (2006). Autistic behavior in children with fragile X syndrome: prevalence, stability, and the impact of FMRP .
  25. (2007). Behav Pediatr.
  26. (2007). Behavioral alterations in mice lacking the translation repressor 4E-BP2. Neurobiol Learn Mem.
  27. Behavioral differences among subjects with Prader-Willi syndrome and type I or type II deletion and maternal disomy.
  28. Biochemical evidence for the association of fragile X mental retardation protein with brain polyribosomal ribonucleoparticles.
  29. Biochemical mechanisms for translational regulation in synaptic plasticity.
  30. (1999). Capdependent translation initiation in eukaryotes is regulated by a molecular mimic of eIF4G. Mol Cell.
  31. CGG-repeat length and neuropathological and molecular correlates in a mouse model for fragile Xassociated tremor/ataxia syndrome.
  32. (1993). Clinical and molecular studies in fragile X patients with a Prader-Willi-like phenotype.
  33. Compartmentalized synthesis and degradation of proteins in neurons.
  34. Contribution of mGluR and Fmr1 functional pathways to neurite morphogenesis, craniofacial development and fragile X syndrome. Hum Mol Genet.
  35. Correction of fragile X syndrome in mice.
  36. CYFIP/Sra-1 controls neuronal connectivity in Drosophila and links the Rac1 GTPase pathway to the fragile X protein.
  37. (2006). Decreased expression of the GABAA receptor in fragile X syndrome. Brain Res.
  38. Delayed stabilization of dendritic spines in fragile X mice.
  39. (2007). Dendritic mRNA: transport, translation and function. Nat Rev Neurosci.
  40. Deregulation of EIF4E: a novel mechanism for autism.
  41. (2007). Detection of a novel familial deletion of four genes between BP1 and BP2 of the Prader-Willi/Angelman syndrome critical region by oligo-array CGH in a child with neurological disorder and speech impairment. Cytogenet Genome Res.
  42. dFMRP and Caprin, translational regulators of synaptic plasticity, control the cell cycle at the Drosophila mid-blastula transition.
  43. (2011). Differential expression of FMR1, FXR1 and FXR2 proteins in human brain and testis. Hum Mol Genet.
  44. Differential usage of transcriptional start sites and polyadenylation sites in FMR1 premutation alleles.
  45. Dual regulation of fragile X mental retardation protein by group I metabotropic glutamate receptors controls translation-dependent epileptogenesis in the hippocampus.
  46. Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression.
  47. Dysregulated metabotropic glutamate receptor-dependent translation of AMPA receptor and postsynaptic density-95 mRNAs at synapses in a mouse model of fragile X syndrome.
  48. Elevated FMR1 mRNA in premutation carriers is due to increased transcription.
  49. Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragile-X syndrome.
  50. Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD.
  51. Epidemiology of autistic disorder and other pervasive developmental disorders.
  52. (2002). Epilepsy in fragile X syndrome. Dev Med Child Neurol.
  53. Evidence that fragile X mental retardation protein is a negative regulator of translation. Hum Mol Genet.
  54. (2006). Expression profiling suggests underexpression of the GABA(A) receptor subunit delta in the fragile X knockout mouse model. Neurobiol Dis.
  55. FMR1 RNA within the intranuclear inclusions of fragile X-associated tremor/ataxia syndrome (FXTAS).
  56. (2003). FMRP is implicated in both basal and activity-dependent local protein synthesis (Hou et al. 2006; Kao et al. 2010; Lu et al. 2004; Muddashetty et al. 2007; Napoli et al. 2008;P a r ke ta l .2008; Zalfa et al.
  57. (2007). FMRP mediates mGluR5-dependent translation of amyloid precursor protein. PLoS Biol.
  58. FMRP phosphorylation reveals an immediate-early signaling pathway triggered by group I mGluR and mediated by PP2A.
  59. (2003). Following studies detected FMRP either co-fractionating with polysomes (Ceman
  60. Fragile X mental retardation protein (FMRP) binds specifically to the brain cytoplasmic RNAs BC1/BC200 via a novel RNA-binding motif.
  61. Fragile X mental retardation protein control of neuronal mRNA metabolism: insights into mRNA stability. Mol Cell Neurosci.
  62. Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack. Nat Neurosci.
  63. Fragile X mental retardation protein FMRP and the RNA export factor NXF2 associate with and destabilize
  64. Fragile X mental retardation protein is associated with translating polyribosomes in neuronal cells.
  65. Fragile X syndrome and autism at the intersection of genetic and neural networks.
  66. (1992). Fragile X syndrome without CCG amplification has an FMR1 deletion. Nat Genet.
  67. Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function.
  68. (2007). Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1. Lancet Neurol.
  69. Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation.
  70. (2005). From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome. Nat Rev Neurosci.
  71. (2007). GABA subunits Mouse cortex; Drosophila. mRNA levels are reduced but a direct evidence on their different stability is not available Gantois et al. 2006; D’Hulst et al. 2006; Dictenberg
  72. hnRNP C promotes APP translation by competing with FMRP for APP mRNA recruitment to P bodies. Nat Struct Mol Biol.
  73. Hypersensitivity to mGluR5 and ERK1/2 leads to excessive protein synthesis in the hippocampus of a mouse model of fragile X syndrome.
  74. In vivo brain anatomy of adult males with Fragile X syndrome: an MRI study.
  75. Increased threshold for spike-timing-dependent plasticity is caused by unreliable calcium signaling in mice lacking fragile X gene FMR1.
  76. Kinesin transports RNA: isolation and characterization of an RNA-transporting granule.
  77. (2006). Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses. Mol Cell Neurosci.
  78. (2005). Localization of FMRP-associated mRNA granules and requirement of microtubules for activity-dependent trafficking in hippocampal neurons. Genes Brain Behav.
  79. (1998). Macroorchidism in FMR1 knockout mice is caused by increased Sertoli cell proliferation during testicular development. Endocrinology.
  80. (2009). Making synaptic plasticity and memory last: mechanisms of translational regulation. Genes Dev.
  81. (2010). Med Genet B Neuropsychiatr Genet.
  82. mental retardation protein controls trailer hitch expression and cleavage furrow formation in Drosophila embryos.
  83. Metabotropic glutamate receptor activation regulates fragile x mental retardation protein and FMR1 mRNA localization differentially in dendrites and at synapses.
  84. Microarray based comparative genomic hybridization testing in deletion bearing patients with Angelman syndrome: genotype– phenotype correlations.
  85. Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome.
  86. Mouse models of fragile x-associated tremor ataxia.
  87. (1997). Neurodevelop Disord (2011) 3:257–269Feng
  88. Neurodevelopmental disorders involving genomic imprinting at human chromosome 15q11-q13. Neurobiol Dis.
  89. (1995). Neurodevelopmental effects of the FMR-1 full mutation in humans. Nat Med.
  90. Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers.
  91. (2006). Neuropathology of fragile X-associated tremor/ataxia syndrome
  92. (1998). No evidence for disruption of normal patterns of mRNA localization in dendrites or dendritic transport of recently synthesized mRNA in FMR1 knockout mice, a model for human fragile-X mental retardation syndrome.
  93. (1993). Ofinterest,a subgroupofpatientswithFXSshowsa PWSlikephenotype withseverehyperphagia,obesity, short stature, short fingers and toes, and hypogonadism (de Vries
  94. Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroom body defects in a Drosophila model of fragile X syndrome.
  95. Phosphorylation influences the translation state of FMRPassociated polyribosomes. Hum Mol Genet.
  96. (2006). polysomes or granules: FMRP in neuronal protein synthesis. Curr Opin Neurobiol.
  97. Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome.
  98. (2008). Quantitative proteomic analysis of primary neurons reveals diverse changes in synaptic protein content in fmr1 knockout mice.
  99. (2000). Rare variants in the promoter of the fragile X syndrome gene (FMR1). Mol Cell Probes.
  100. Reduced FMR1 mRNA translation efficiency in fragile X patients with premutations.
  101. (2001). Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers. Hum Mol Genet.
  102. Regional FMRP deficits and large repeat expansions into the full mutation range in a new Fragile X premutation mouse model.
  103. Regulation of synaptic structure and function by FMRP-associated microRNAs miR-125b and miR-132.
  104. (2008). Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat Med.
  105. Reversing neurodevelopmental disorders in adults.
  106. RNA cargoes associating with FMRP reveal deficits in cellular functioning
  107. RNA granules.
  108. (2009). RNA-mediated pathogenesis in fragile X-associated disorders. Neurosci Lett.
  109. RNAbinding proteins hnRNPA2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS.
  110. Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression.
  111. Role of Pur alpha in targeting mRNA to sites of translation in hippocampal neuronal dendrites.
  112. S6K1 phosphorylates and regulates fragile X mental retardation protein (FMRP) with the neuronal protein synthesisdependent mammalian target of rapamycin (mTOR) signaling cascade.
  113. (2008). Secondary medical diagnosis in fragile X syndrome with and without autism spectrum disorder.
  114. (1996). Specific sequences in the fragile X syndrome protein FMR1 and the FXR proteins mediate their binding to 60S ribosomal subunits and the interactions among them. Mol Cell Biol.
  115. Subcellular mRNA localization in animal cells and why it matters.
  116. Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP .
  117. (2010). The first one (A) proposes that the kinase ERK1/2 activation releases FMRP translational inhibition (Osterweil et al.
  118. (2009). The FMR1 gene and fragile X-associated tremor/ataxia syndrome.
  119. (2004). The fragile X mental retardation protein has nucleic acid chaperone properties. Nucleic Acids Res.
  120. (2001). The fragile X mental retardation protein inhibits translation via interacting with mRNA. Nucleic Acids Res.
  121. (2007). The fragile X mental retardation protein is a molecular adaptor between the neurospecific KIF3C kinesin and dendritic RNA granules. Hum Mol Genet.
  122. The fragile X mental retardation protein is required for type-I metabotropic glutamate receptordependent translation of PSD-95.
  123. (2007). The fragile X mental retardation protein-RNP granules show an mGluR-dependent localization in the post-synaptic spines. Mol Cell Neurosci.
  124. (2002). The fragile X premutation: into the phenotypic fold. Curr Opin Genet Dev.
  125. (2011). The fragile X protein controls microtubule-associated protein 1B translation and microtubule stability in brain neuron development.
  126. The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses.
  127. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP .
  128. (2004). The mGluR theory of fragile X mental retardation. Trends Neurosci.
  129. (2007). The mTOR pathway could play a role in FXS. First, the fine tuning of the PP2A/S6K activity through the mTOR signaling modulates the phosphorylation state of FMRP (Narayanan
  130. The RNA binding and transport proteins staufen and fragile X mental retardation protein are expressed by rat primary afferent neurons and localize to peripheral and central axons.
  131. The state of synapses in fragile X syndrome.
  132. (2004). The synaptic distribution of FMRP increases upon the activation of the group I mGluRs. In fact, in response to DHPG, the dendritic transport of Fmr1 mRNA is enhanced, and FMRP is newly synthesized in close proximity to mGluR5 (Antar
  133. (2007). The W ASP-W A VE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol.
  134. (2003). This suggests that FMRP can take part in a variety of mRNPs and is possibly influenced by its phosphorylation state (Ceman
  135. (1990). Thyroid function in fragile-X syndrome males.
  136. Translational control of long-lasting synaptic plasticity and memory.
  137. (1995). Translational suppression by trinucleotide repeat expansion at FMR1.
  138. Transmembrane receptor DCC associates with protein synthesis machinery and regulates translation.