Divergent dysregulation of gene expression in murine models of fragile X syndrome and tuberous sclerosis (original) (raw)
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Molecular Mechanisms of Synaptic Dysregulation in Fragile X Syndrome and Autism Spectrum Disorders
Frontiers in Molecular Neuroscience, 2019
Fragile X syndrome (FXS) is the most common form of monogenic hereditary cognitive impairment. FXS patient exhibit a high comorbidity rate with autism spectrum disorders (ASDs). This makes FXS a model disease for understanding how synaptic dysregulation alters neuronal excitability, learning and memory, social behavior, and more. Since 1991, with the discovery of fragile X mental retardation 1 (FMR1) as the sole gene that is mutated in FXS, thousands of studies into the function of the gene and its encoded protein FMR1 protein (FMRP), have been conducted, yielding important information regarding the pathophysiology of the disease, as well as insight into basic synaptic mechanisms that control neuronal networking and circuitry. Among the most important, are molecular mechanisms directly involved in plasticity, including glutamate and γaminobutyric acid (GABA) receptors, which can control synaptic transmission and signal transduction, including short-and long-term plasticity. More recently, several novel mechanisms involving growth factors, enzymatic cascades and transcription factors (TFs), have been proposed to have the potential of explaining some of the synaptic dysregulation in FXS. In this review article, I summarize the main mechanisms proposed to underlie synaptic disruption in FXS and ASDs. I focus on studies conducted on the Fmr1 knockout (KO) mouse model and on FXS-human pluripotent stem cells (hPSCs), emphasizing the differences and even contradictions between mouse and human, whenever possible. As FXS and ASDs are both neurodevelopmental disorders that follow a specific time-course of disease progression, I highlight those studies focusing on the differential developmental regulation of synaptic abnormalities in these diseases.
Changes in Synaptic Protein Content and Signaling in a Mouse Model of Fragile X Syndrome
Changes in synaptic protein content and signaling in a mouse model of Fragile X Syndrome Fragile X Syndrome (FXS) is the most common inherited cause of intellectual disability (ID) in males and a significant cause of ID in females. In addition to ID, affected children may also exhibit hyperactivity, extreme anxiety in multiple forms, poor social communication (including poor eye contact and poor pragmatics), and other autism spectrum behaviors such as restricted interests and repetitive patterns of behavior. FXS is also characterized by a variety of distinct physical characteristics, including an enlarged head, protruding ears, and joint laxity (Learning About Fragile X Syndrome, 2013). Furthermore, a hallmark neuroanatomical abnormality of FXS brain is the overabundance of long, thin, and "tortuous" dendritic spinesthe postsynaptic aspect of excitatory glutamatergic synapses-which suggests that a fundamental synaptic abnormality underlies the syndrome's many symptoms. Nearly all cases of FXS are caused by transcriptional silencing of the Fragile X mental retardation I (Fmr1) gene on the X chromosome, which results from a CGG triplet repeat expansion of more than 200 copies within a non-protein coding segment of the gene corresponding to the 5' untranslated region of the transcribed messenger RNA (mRNA). However, some rare cases of FXS are caused by mutations in protein coding regions of Fmr1 (Collins et al., 2010). This abnormally expanded DNA segment inactivates the Fmr1 gene, leading to the lack of expression of the gene's encoded protein, the Fragile X mental retardation protein (FMRP) (Learning About Fragile X Syndrome, 2013). In accordance with this genetic inactivation, the Fmr1 knockout mouse was developed for use as an important tool in FXS research. Knockout mice exhibit similar behavioral and molecular phenotypes to humans with FXS, including learning deficits, hyperactivity, audiogenic seizures (thought to be a parallel to
2016
Changes in synaptic protein content and signaling in a mouse model of Fragile X Syndrome Fragile X Syndrome (FXS) is the most common inherited cause of intellectual disability (ID) in males and a significant cause of ID in females. In addition to ID, affected children may also exhibit hyperactivity, extreme anxiety in multiple forms, poor social communication (including poor eye contact and poor pragmatics), and other autism spectrum behaviors such as restricted interests and repetitive patterns of behavior. FXS is also characterized by a variety of distinct physical characteristics, including an enlarged head, protruding ears, and joint laxity (Learning About Fragile X Syndrome, 2013). Furthermore, a hallmark neuroanatomical abnormality of FXS brain is the overabundance of long, thin, and "tortuous" dendritic spinesthe postsynaptic aspect of excitatory glutamatergic synapses-which suggests that a fundamental synaptic abnormality underlies the syndrome's many symptoms. Nearly all cases of FXS are caused by transcriptional silencing of the Fragile X mental retardation I (Fmr1) gene on the X chromosome, which results from a CGG triplet repeat expansion of more than 200 copies within a non-protein coding segment of the gene corresponding to the 5' untranslated region of the transcribed messenger RNA (mRNA). However, some rare cases of FXS are caused by mutations in protein coding regions of Fmr1 (Collins et al., 2010). This abnormally expanded DNA segment inactivates the Fmr1 gene, leading to the lack of expression of the gene's encoded protein, the Fragile X mental retardation protein (FMRP) (Learning About Fragile X Syndrome, 2013). In accordance with this genetic inactivation, the Fmr1 knockout mouse was developed for use as an important tool in FXS research. Knockout mice exhibit similar behavioral and molecular phenotypes to humans with FXS, including learning deficits, hyperactivity, audiogenic seizures (thought to be a parallel to
Frontiers in Molecular Neuroscience, 2017
Fragile X syndrome (FXS) is a genetic disorder due to the silencing of the Fmr1 gene, causing intellectual disability, seizures, hyperactivity, and social anxiety. All these symptoms result from the loss of expression of the RNA binding protein fragile X mental retardation protein (FMRP), which alters the neurodevelopmental program to abnormal wiring of specific circuits. Aberrant mRNAs translation associated with the loss of Fmr1 product is widely suspected to be in part the cause of FXS. However, precise gene expression changes involved in this disorder have yet to be defined. The objective of this study was to identify the set of mistranslated mRNAs that could contribute to neurological deficits in FXS. We used the RiboTag approach and RNA sequencing to provide an exhaustive listing of genes whose mRNAs are differentially translated in hippocampal CA1 pyramidal neurons as the integrative result of FMRP loss and subsequent neurodevelopmental adaptations. Among genes differentially regulated between adult WT and Fmr1 −/y mice, we found enrichment in FMRP-binders but also a majority of non-FMRP-binders. Interestingly, both up-and down-regulation of specific gene expression is relevant to fully understand the molecular deficiencies triggering FXS. More importantly, functional genomic analysis highlighted the importance of genes involved in neuronal connectivity. Among them, we show that Klk8 altered expression participates in the abnormal hippocampal dendritic spine maturation observed in a mouse model of FXS.
Gene Expression Profiles in a Transgenic Animal Model of Fragile X Syndrome
Neurobiology of Disease, 2002
Fragile X syndrome is the most common inherited form of mental retardation. Although this syndrome originates from the absence of the RNA-binding protein FMRP, the molecular mechanisms underlying the cognitive deficits are unknown. The expression pattern of 6789 genes was studied in the brains of wild-type and FMR1 knockout mice, a fragile X syndrome animal model that has been associated with cognitive deficits. Differential expression of more than twofold was observed for the brain mRNA levels of 73 genes. Differential expression of nine of these genes was confirmed by real-time quantitative reverse transcription-polymerase chain reaction and by in situ hybridization. In addition to corroborating the microarray data, the in situ hybridization analysis showed distinct spatial distribution patterns of microtubule-associated protein 2 and amyloid beta precursor protein. A number of differentially expressed genes associated with the fragile X syndrome phenotype have been previously involved in other memory or cognitive disorders.
Molecular Brain Research, 2000
We sought to determine whether the fragile X mental retardation gene fmr1 is regulated in long-term potentiation (LTP) and electroconvulsive shock (ECS). In situ hybridization of fmr1 mRNA in hippocampus of rats given LTP in vivo showed no change in fmr1 mRNA levels relative to control. However, ECS induced a selective increase in fmr1 mRNA expression in the dentate gyrus (DG) granule cell layer at 6 h post-ECS. The ECS paradigm may unmask relevant activity-dependent regulatory mechanisms that modulate fmr1 gene transcription in vivo.
Brain Research, 2015
Fragile X syndrome is the most common inherited form of mental retardation and autism. It is caused by a reduction or elimination of the expression of fragile X mental retardation protein (FMRP). Because fragile X syndrome is a neurodevelopmental disorder, it is important to fully document the cell type expression in the developing CNS to provide a better understanding of the molecular function of FMRP, and the pathogenesis of the syndrome. We investigated FMRP expression in the brain using double-labeling immunocytochemistry and cell type markers for neurons (NeuN), astrocytes (S100β), microglia (Iba-1), and oligodendrocyte precursor cells (NG2). The hippocampus, striatum, cingulate cortex, retrosplenial cortex, corpus callosum and cerebellum were assessed in wild-type C57/BL6 mice at postnatal days 0, 10, 20, and adult. Our results demonstrate that FMRP is ubiquitously expressed in neurons at all times and brain regions studied, except for corpus callosum where FMRP was predominantly present in astrocytes at all ages. FMRP expression in Iba-1 and NG2-positive cells was detected at postnatal day 0 and 10 and gradually decreased to very low or undetectable levels in postnatal day 20 and adult mice. Our results reveal that in addition to continuous and extensive expression in neurons in the immature and mature brain, FMRP is also present in astrocytes, oligodendrocyte precursor cells, and microglia during the early and mid-postnatal developmental stages of brain maturation. Prominent expression of FMRP in glia during these crucial stages of brain development suggests an important contribution to normal brain function, and in its absence, to the fragile X phenotype.
Brain Sciences
Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene, which encodes a protein with a critical role in synaptic plasticity. The molecular abnormality underlying FMR1 silencing, CGG repeat expansion, is well characterized; however, delineation of the pathway from DNA to RNA to protein using biosamples from well characterized patients with FXS is limited. Since FXS is a common and prototypical genetic disorder associated with intellectual disability (ID) and autism spectrum disorder (ASD), a comprehensive assessment of the FMR1 DNA-RNA-protein pathway and its correlations with the neurobehavioral phenotype is a priority. We applied nine sensitive and quantitative assays evaluating FMR1 DNA, RNA, and FMRP parameters to a reference set of cell lines representing the range of FMR1 expansions. We then used the most informative of these assays on blood and buccal specimens from cohorts of patients with different FMR1 expansions, with emphasis on those with FXS (N = 42 total, N =...