Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fragile X syndrome is a common form of inherited mental retardation caused by the loss of FMR1 expression. The FMR1 gene encodes an RNA-binding protein that associates with translating ribosomes and acts as a negative translational regulator. In Drosophila, the fly homolog of the FMR1 protein (dFMR1) binds to and represses the translation of an mRNA encoding of the microtuble-associated protein Futsch. We have isolated a dFMR1-associated complex that includes two ribosomal proteins, L5 and L11, along with 5S RNA. The dFMR1 complex also contains Argonaute2 (AGO2) and a Drosophila homolog of p68 RNA helicase (Dmp68). AGO2 is an essential component for the RNA-induced silencing complex (RISC), a sequence-specific nuclease complex that mediates RNA interference (RNAi) in Drosophila. We show that Dmp68 is also required for efficient RNAi. We further show that dFMR1 is associated with Dicer, another essential component of the RNAi pathway, and microRNAs (miRNAs) in vivo, suggesting that dFMR1 is part of the RNAi-related apparatus. Our findings suggest a model in which the RNAi and dFMR1-mediated translational control pathways intersect in Drosophila. Our findings also raise the possibility that defects in an RNAi-related machinery may cause human disease.
 ...
PMID:A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins. 1236 61

Fragile X syndrome is the most common heritable form of mental retardation caused by loss-of-function mutations in the FMR1 gene. The FMR1 gene encodes an RNA-binding protein that associates with translating ribosomes and acts as a negative translational regulator. Recent work in Drosophila melanogaster has shown that the fly homolog of FMR1 (dFMR1) plays an important role in regulating neuronal morphology, which may underlie the observed deficits in behaviors of dFMR1 mutant flies. Biochemical analysis has revealed that dFMR1 forms a complex that includes ribosomal proteins and, surprisingly, Argonaute2 (AGO2), an essential component of the RNA-induced silencing complex (RISC) that mediates RNA interference (RNAi) in Drosophila. dFMR1 also associates with Dicer, another essential processing enzyme of the RNAi pathway. Moreover, both a micro-RNA (miRNA) and short interfering RNAs (siRNAs) can coimmunoprecipitate with dFMR1. Together these findings suggest that dFMR1 functions in an RNAi-related apparatus to regulate the expression of its target genes at the level of translation. These findings raise the possibility that Fragile X syndrome may be the result of a protein synthesis abnormality caused by a defect in an RNAi-related apparatus. Because the core mechanisms of complex behaviors such as learning and memory and circadian rhythms appear to be conserved, studies of Fragile X syndrome using Drosophila as a model provide an economy-of-scale for identifying biological processes that likely underlie the abnormal morphology of dendritic spines and behavioral disturbances observed in Fragile X patients.
 ...
PMID:RNA interference: a new mechanism by which FMRP acts in the normal brain? What can Drosophila teach us? 1499 91

Fragile X syndrome, a common form of inherited mental retardation, is caused by the loss of the Fragile X mental retardation protein (FMRP). FMRP, which may regulate translation in neurons, not only associates with specific messenger RNAs (mRNAs) and with microRNAs (miRNAs), but also associates with the components of the miRNA pathway, including the Dicer and Argonaute proteins. It has been proposed that FMRP regulates the translation of its mRNA targets through miRNAs. In this chapter, we describe the protocol to identify the mRNAs and miRNAs associated with FMRP in vivo. The same method could also be applied to other RNA-binding proteins interacting with specific mRNAs or miRNAs.
 ...
PMID:Identification of messenger RNAs and microRNAs associated with fragile X mental retardation protein. 1695 81

Fragile X syndrome, a common form of inherited mental retardation, is caused by the loss of fragile X mental retardation protein (FMRP). FMRP, which may regulate translation in neurons, associates not only with specific mRNAs and microRNAs (miRNA), but also with components of the miRNA pathway, including Dicer and Argonaute proteins. In Drosophila, dFmr1 is also known to be involved in germ cell and oocyte specification; however, the question of whether dFmr1 is required for controlling the fate of germline stem cells (GSCs) has gone unanswered. Here we show that dFmr1 is required for both GSC maintenance and repressing differentiation. Furthermore, we demonstrate that in Drosophila ovary, dFmr1 protein interacts with Argonaute protein 1 (AGO1), a key component of the miRNA pathway. Thus dFmr1 could modulate the fate of GSCs, likely via the miRNA pathway. Our results provide the first evidence that FMRP might be involved in the regulation of adult stem cells.
 ...
PMID:Fragile X mental retardation protein modulates the fate of germline stem cells in Drosophila. 1751 21

Fragile X syndrome is the most common form of inherited mental retardation caused by loss of the fragile X mental retardation protein 1 (FMRP). The detailed molecular pathways underlying the pathogenesis of this disorder remain incompletely understood. Here, we show that miR-124a, a nervous-system-specific miRNA, is associated with the Drosophila homolog of FMRP (dFMR1) in vivo. Ectopic expression of wild-type but not mutant miR-124a precursors decreased dendritic branching of dendritic arborization sensory neurons, which was partially rescued by the loss of dFMR1 activity, suggesting that the biogenesis and/or function of miR-124a are partially dependent on dFMR1. Indeed, in contrast with the complete loss of mature miR-124a in Dicer-1 mutants, steady-state levels of endogenous or ectopically expressed mature miR-124a were partially reduced in dfmr1 mutants, whereas the level of pre-miR-124a increased. This effect could be explained in part by the reduced abundance of the Dicer-1-Ago1 complex in the absence of dFMR1. These findings suggest a modulatory role for dFMR1 to maintain proper levels of miRNAs during neuronal development.
 ...
PMID:The steady-state level of the nervous-system-specific microRNA-124a is regulated by dFMR1 in Drosophila. 1900 53

Fragile X syndrome is caused by an absence of the protein product of the fragile X mental retardation gene (FMR1). The fragile X mental retardation protein (FMRP) is an RNA-binding protein that regulates translation of associated mRNAs; however, the mechanism for this regulation remains unknown. Constitutively, phosphorylated FMRP (P-FMRP) is found associated with stalled untranslating polyribosomes, and translation of at least one mRNA is down-regulated when FMRP is phosphorylated. Based on our hypothesis that translational regulation by P-FMRP is accomplished through association with the microRNA (miRNA) pathway, we developed a phospho-specific antibody to P-FMRP and showed that P-FMRP associates with increased amounts of precursor miRNAs (pre-miRNA) compared with total FMRP. Furthermore, P-FMRP does not associate with Dicer or Dicer-containing complexes in coimmunoprecipitation experiments or in an in vitro capture assay using a P-FMRP peptide sequence bound to agarose beads. These data show that Dicer-containing complexes bind FMRP at amino acids 496-503 and that phosphorylation disrupts this association with a consequent increase in association with pre-miRNAs. In sum, we propose that in addition to regulating translation, phosphorylation of FMRP regulates its association with the miRNA pathway by modulating association with Dicer.
 ...
PMID:Phosphorylation of FMRP inhibits association with Dicer. 1915 29

FXR1P is one of two autosomal paralogs of the fragile X mental retardation protein FMRP. The absence of FMRP causes fragile X syndrome, the leading cause of hereditary mental retardation. FXR1P plays an important role in normal muscle development and has been implicated in facioscapulohumeral muscular dystrophy (FSHD). Its absence also causes cardiac abnormalities in both mice and zebrafish. To examine miRNA-mediated regulation of FMRP and FXR1P, we studied their expression in a conditional Dicer knockdown cell line, DT40. We found that FXR1P, but not FMRP, is significantly increased upon Dicer knockdown and the consequent reduction of miRNAs, suggesting that FXR1P is regulated by miRNAs while FMRP is not in DT40 cells. Expression of a luciferase reporter bearing the 3' untranslated region (3'UTR) of FXR1 was significantly increased in the absence of miRNAs, confirming miRNA-mediated regulation of FXR1P, while a luciferase reporter bearing the FMR1 3'UTR was not. We identified one of the regulatory regions in the 3'UTR of FXR1 by removing a conserved, 8-nucleotide miRNA seed sequence common to miRNAs 25, 32, 92, 363, and 367 and demonstrated loss of miRNA-mediated suppression. Treatment with specific miRNA hairpin inhibitors to each of the miRNAs in the seed sequence showed that miRs 92b, 363, and 367 regulated FXR1P expression. Accordingly, overexpression of the miRNA 367 mimic significantly decreased endogenous FXR1P expression in human cell lines HEK-293T and HeLa. We report for the first time that FXR1P is regulated through miRNA binding, with one site being the miR-25/32/92/363/367 seed sequence.
 ...
PMID:Fragile X protein family member FXR1P is regulated by microRNAs. 2051 10

Fragile X syndrome is one of the most common forms of inherited intellectual disability. It is caused by mutations of the Fragile X mental retardation 1(FMR1) gene, resulting in either the loss or abnormal expression of the Fragile X mental retardation protein (FMRP). Recent research showed that FMRP participates in non-coding RNA pathways and plays various important roles in physiology, thereby extending our knowledge of the pathogenesis of the Fragile X syndrome. Initial studies showed that the Drosophila FMRP participates in siRNA and miRNA pathways by interacting with Dicer, Ago1 and Ago2, involved in neural activity and the fate determination of the germline stem cells. Subsequent studies showed that the Drosophila FMRP participates in piRNA pathway by interacting with Aub, Ago1 and Piwi in the maintenance of normal chromatin structures and genomic stability. More recent studies showed that FMRP is associated with lncRNA pathway, suggesting a potential role for the involvement in the clinical manifestations. In this review, we summarize the novel findings and explore the relationship between FMRP and non-coding RNA pathways, particularly the piRNA pathway, thereby providing critical insights on the molecular pathogenesis of Fragile X syndrome, and potential translational applications in clinical management of the disease.
 ...
PMID:Fragile X mental retardation protein participates in non-coding RNA pathways. 2942 1