Rare fragile sites on chromosomes are the archetypal dynamic mutations. They involve large expansions of the microsatellite CCG or AT-rich minisatellites. The mutation process is an increase in repeat-unit number from within a normal range, through a premutation range, up to full mutation where the fragile site is expressed. Full mutations can inactivate genes and are regions of genomic instability. Common fragile sites, in particular, might have a role in oncogenesis by facilitating gene inactivation through chromosomal deletion or amplification, but this requires further exploration. The mechanisms behind the changes that give rise to the cytogenetic manifestation of chromosomal fragility are now beginning to be understood. 相似文献
Mental retardation (MR) is a developmental brain disorder characterized by impaired cognitive performance and adaptive skills that affects 1–2% of the population. During the last decade, a large number of genes have been cloned that cause MR upon mutation in humans. The causal role of these genes provides an excellent starting point to investigate the cellular, neurobiological and behavioral alterations and mechanisms responsible for the cognitive impairment in mentally retarded persons. However, studies on Down syndrome (DS) reveal that overexpression of a cluster of genes and various forms of MR that are caused by single-gene mutations, such as fragile X (FraX), Rett, Coffin-Lowry, Rubinstein–Taybi syndrome and non-syndromic forms of MR, causes similar phenotypes. In spite of the many differences in the manifestation of these forms of MR, evidence converges on the proposal that MR is primarily due to deficiencies in neuronal network connectivity in the major cognitive centers in the brain, which secondarily results in impaired information processing. Although MR has been largely regarded as a brain disorder that cannot be cured, our increased understanding of the abnormalities and mechanisms underlying MR may provide an avenue for the development of therapies for MR. In this review, we discuss the neurobiology underlying MR, with a focus on FraX and DS 相似文献
The past few years have seen an increased number of articles using Drosophila as a model system to study fragile X syndrome. Phenotypic analyses have demonstrated an array of neuronal and behavioral defects similar to the phenotypes reported in mouse models as well as human patients. The availability of both cellular and molecular tools along with the power of genetics makes the tiny fruit fly a premiere model in elucidating the molecular basis of fragile X syndrome. Here, we summarize the advances made in recent years in the characterization of fragile X Drosophila models and the identification of new molecular partners in neural development. 相似文献
Fragile X syndrome (FXS) is the most prevalent form of heritable mental retardation. It arises from a mutation in the FMR1 gene on the X chromosome that interferes with expression of fragile X mental retardation protein (FMRP) and leads to a wide range of behavioural and cognitive deficits. Previous studies have shown a deficit in basic visual perceptual processing as well as spatial abilities in FXS. How such a deficit may impact spatial navigation remains unknown. The current study extended previous research by evaluating spatial learning and memory using both virtual and physical versions of Hebb-Williams mazes, which allows for testing of humans and animals under comparable conditions. We compared the performance of individuals affected by FXS to typically developing individuals of equivalent mental age as well as the performance of Fmr1 knockout mice to wild-type control mice on the same maze problems. In human participants, performance of the comparison group improved across trials, showing expected significant decreases in both errors and latency. In contrast, the performance of the fragile X group remained at similar levels across trials. Although wild-type control mice made significantly fewer errors than the Fmr1 knockout mice, latencies were not statistically different between the groups. These findings suggest that affected humans and mice show similar spatial learning deficits attributable to the lack of FMRP. The implications of these data are discussed including the notion that Hebb-Williams mazes may represent a useful tool to examine the impact of pharmacological interventions on mitigating or reversing the symptoms associated with FXS. 相似文献
Perineuronal nets (PNNs) are mesh-like structures on the surfaces of parvalbumin-expressing inhibitory and other neurons, and consist of proteoglycans such as aggrecan, brevican, and neurocan. PNNs regulate the Excitatory/Inhibitory (E/I) balance in the brain and are formed at the closure of critical periods of plasticity during development. PNN formation is disrupted in Fragile X Syndrome, which is caused by silencing of the fragile X messenger ribonucleoprotein 1 (Fmr1) gene and loss of its protein product FMRP. FXS is characterized by impaired synaptic plasticity resulting in neuronal hyperexcitability and E/I imbalance. Here, we investigate how PNN formation is altered in FXS. PNNs are reduced in Fmr1 KO mouse brain when examined by staining for the lectin Wisteria floribunda agglutin (WFA) and aggrecan. Examination of PNNs by WFA staining at P14 and P42 in the hippocampus, somatosensory cortex, and retrosplenial cortex shows that they were reduced in these brain regions at P14 but mostly less so at P42 in Fmr1 KO mice. However, some differential FMRP regulation of PNN development in these brain regions persists, perhaps caused by asynchrony in PNN development between brain regions in wild-type animals. During development, aggrecan PNN levels in the brain were reduced in all brain regions in Fmr1 KO mice. Aggrecan mRNA levels were unchanged at these times, suggesting that FMRP is normally an activator of aggrecan mRNA translation. This hypothesis is buttressed by the observations that FMRP binds aggrecan mRNA and that ribosome profiling data show that aggrecan mRNA is associated with reduced numbers of ribosomes in Fmr1 KO mouse brain, indicating reduced translational efficiency. Moreover, aggrecan mRNA poly(A) tail length is also reduced in Fmr1 KO mouse brain, suggesting a relationship between polyadenylation and translational control. We propose a model where FMRP modulates PNN formation through translational up-regulation of aggrecan mRNA polyadenylation and translation. 相似文献
Fragile X syndrome is caused by the absence of the fragile X mental-retardation protein (FMRP), an mRNA-binding protein, which may play important roles in the regulation of dendritic mRNA localization and/or synaptic protein synthesis. We have recently applied high-resolution fluorescence imaging methods to document the presence, motility and activity-dependent regulation of FMRP granule trafficking in dendrites and spines of cultured hippocampal neurons. In this study, we show that FMRP granules distribute to F-actin-rich compartments, including filopodia, spines and growth cones during the staged development of hippocampal neurons in culture. Fragile X mental-retardation protein granules were shown to colocalize with ribosomes, ribosomal RNA and MAP1B mRNA, a known FMRP target, which encodes a protein important for microtubule and actin stabilization. The levels of FMRP within dendrites were reduced by disruption of microtubule dynamics, but not by disruption of F-actin. Direct measurements of FMRP transport kinetics using fluorescence recovery after photobleaching in living neurons showed that microtubules were required to induce the mGluR-dependent translocation into dendrites. This study provides further characterization of the composition and regulated trafficking of FMRP granules in dendrites of hippocampal neurons. 相似文献
The small GTPase Rac1 is well known for regulating actin cytoskeleton reorganization in cells. Formation of extensions at the surface of the cell is required for migration and even for cell invasion and metastases. Because an elevated level and hyperactivation of this protein has been associated with metastasis in cancer, direct regulators of Rac1 are currently envisioned as a potential strategy to treat certain cancers. Less research, however, has been done regarding the role of this small GTP‐binding protein in brain development, where it has an important role in dendritic spine morphogenesis through the regulation of actin. Alteration of dendritic development and spinogenesis has been often associated with mental disorders. Rac1 is associated with and required for learning and the formation of memories in the brain. Rac1 appears to be dysregulated in certain neurodevelopmental disorders that present all these three alterations: mental retardation, atypical synaptic plasticity and aberrant spine morphology. Thus, to develop novel therapies for rescuing cognitive impairment, a reasonable approach might be to target this protein, Rac1, which plays a pivotal role in directing signals that regulate actin dynamics, which in turn might have an effect in spine cytoarchitecture and synaptic function. It is possible that novel drugs that regulate Rac1 activation and function could modulate actin cytoskeleton and spine dynamics, representing potential candidates to repair intellectual disability in disorders associated with spine abnormalities. Herein, we present a list of the current Rac1 inhibitors that might fulfill this role together with a summary of the latest findings concerning their function as they relate to neuronal studies.
The (CGG)n-repeat in the 5′-untranslated region of the fragile X mental retardation gene (FMR1) gene is polymorphic and may become unstable on transmission to the next generation. In fragile X syndrome, CGG repeat lengths exceed 200, resulting in silencing of FMR1 and absence of its protein product, fragile X mental retardation protein (FMRP). CGG repeat lengths between 55 and 200 occur in fragile X premutation (FXPM) carriers and have a high risk of expansion to a full mutation on maternal transmission. FXPM carriers have an increased risk for developing progressive neurodegenerative syndromes and neuropsychological symptoms. FMR1 mRNA levels are elevated in FXPM, and it is thought that clinical symptoms might be caused by a toxic gain of function due to elevated FMR1 mRNA. Paradoxically, FMRP levels decrease moderately with increasing CGG repeat length in FXPM. Lowered FMRP levels may also contribute to the appearance of clinical problems. We previously reported increases in regional rates of cerebral protein synthesis (rCPS) in the absence of FMRP in an Fmr1 knockout mouse model and in a FXPM knockin (KI) mouse model with 120 to 140 CGG repeats in which FMRP levels are profoundly reduced (80%–90%). To explore whether the concentration of FMRP contributes to the rCPS changes, we measured rCPS in another FXPM KI model with a similar CGG repeat length and a 50% reduction in FMRP. In all 24 brain regions examined, rCPS were unaffected. These results suggest that even with 50% reductions in FMRP, normal protein synthesis rates are maintained. 相似文献
1. Fragile X syndrome, the most common form of inherited mental retardation,iscaused by the lack or dysfunction of fragile X mental retardationprotein (FMRP). The I304N mutation in the RNA-binding domain of FMRP results in an exceptionally severe form of mental retardation.2. We have investigated the subcellular localization of FMRP and its I304N-mutated form in cultured hippocampal neurons and PC12 cells, using immunofluorescence microscopy. In PC12 cells, FMRP was predominantly localized to the cytoplasm and also to the processes after differentiation by NGF.3. In cultured hippocampal neurons, granular labeling was detected along the neuronal processes.4. Double-labeling with synaptophysin antibody revealed FMRP at synaptic sites in neurons.5. The I304N mutation did not appear to affect the transport of FMRP to dendrites or its localization at synaptic sites. Thus, FMRP is a synaptic protein and the severe phenotype observed in the patient with the I304N mutation is not produced by alterations in dendritic transport. 相似文献
Abnormally active glycogen synthase kinase‐3 (GSK3) contributes to pathological processes in multiple psychiatric and neurological disorders. Modeled in mice, this includes increasing susceptibility to dysregulation of mood‐relevant behaviors, impairing performance in several cognitive tasks and impairing adult hippocampal neural precursor cell (NPC) proliferation. These deficits are all evident in GSK3α/β knockin mice, in which serine‐to‐alanine mutations block the inhibitory serine phosphorylation regulation of both GSK3 isoforms, leaving GSK3 hyperactive. It was unknown if both GSK3 isoforms perform redundant actions in these processes, or if hyperactivity of one GSK3 isoform has a predominant effect. To test this, we examined GSK3α or GSK3β knockin mice in which only one isoform was mutated to a hyperactive form. Only GSK3β, not GSK3α, knockin mice displayed heightened vulnerability to the learned helplessness model of depression‐like behavior. Three cognitive measures impaired in GSK3α/β knockin mice showed differential regulation by GSK3 isoforms. Novel object recognition was impaired in GSK3β, not in GSK3α, knockin mice, whereas temporal order memory was not impaired in GSK3α or GSK3β knockin mice, and co‐ordinate spatial processing was impaired in both GSK3α and GSK3β knockin mice. Adult hippocampal NPC proliferation was severely impaired in GSK3β knockin mice, but not impaired in GSK3α knockin mice. Increased activity of GSK3β, in the absence of overexpression or disease pathology, is sufficient to impair mood regulation, novel object recognition and hippocampal NPC proliferation, whereas hyperactive GSK3α individually does not impair these processes. These results show that hyperactivity of the two GSK3 isoforms execute non‐redundant effects on these processes. 相似文献
Studies of the pathophysiology of fragile X syndrome (FXS) have predominantly focused on synaptic and neuronal disruptions in the disease. However, emerging studies highlight the consistency of white matter abnormalities in the disorder. Recent investigations using animal models of FXS have suggested a role for the fragile X translational regulator 1 protein (FMRP) in the development and function of oligodendrocytes, the myelinating cells of the central nervous system. These studies are starting to uncover FMRP's involvement in the regulation of myelin-related genes, such as myelin basic protein, and its influence on the maturation and functionality of oligodendrocyte precursor cells and oligodendrocytes. Here, we consider evidence of white matter abnormalities in FXS, review our current understanding of FMRP's role in oligodendrocyte development and function, and highlight gaps in our knowledge of the pathogenic mechanisms that may contribute to white matter abnormalities in FXS. Addressing these gaps may help identify new therapeutic strategies aimed at enhancing outcomes for individuals affected by FXS. 相似文献
