Mental Retardation In Humans Research Articles

Possible risk factors for Down syndrome and sex chromosomal aneuploidy in Mysore, South India.

BACKGROUND:Down syndrome (DS) and sex chromosomal aneuploidy (SA) are common chromosomal anomalies causing congenital malformations and mental retardation in humans. The well-established risk factor, advanced maternal age, was not found in many of the DS and SA cases in India, while the other possible risk factors have not been well studied. In view of this, the present study has been made.MATERIALS AND METHODS:During the last 5 years, 150 clinically suspected DS and 25 SA cases were referred to our laboratory for chromosome investigation from major hospitals of Mysore city. Chromosome preparations were made from these patients after informed consent was obtained. Well-spread G-banded metaphase plates were analyzed by automated LEICA KARYO software. Two hundred and 100 randomly selected families belonging to different religions were used as controls for the DS and SA cases, respectively. Statistical analysis was carried out using logistic regressionRESULTS:Out of the 150 cases of DS, 122 had free trisomy 21, two were mosaic trisomy 21, and one had translocation. Logistic regression of case-control study of DS children revealed that the odds ratio of uncle-niece marriages, or second cousin marriages, or parents lived in rural region, or exposure of the parents to chemicals, or parents education status, or habits (tobacco/ alcohol used) of father, or mother not undergone prenatal scanning, or mothers with previous abortions were significant when all the variables of that category were used one at a time. Exposure of the parents to chemicals, parents’ educational status, habits (tobacco/alcohol use) of the father, mother not undergone prenatal scanning, and history of previous abortions were significant when all the variables of that category were used one at a time. Similarly, except for consanguinity, history of previous abortions, and mother not undergone prenatal scanning, all other factors showed significant odds ratios in SA cases.CONCLUSION:Besides the known risk factors, consanguinity, region (rural/urban) of residence of parents, exposure of parents to chemicals, educational status of parents, habits of father, prenatal scanning, and reproductive performance of mother are possible risk factors for chromosomal aneuploidy.

The Drosophila Notch Inhibitor and Tumor Suppressor Gene lethal (2) giant discs Encodes a Conserved Regulator of Endosomal Trafficking

Notch signaling is involved in many developmental and pathological processes, and its activity must be precisely controlled in order to prevent aberrant development and disease. We have previously shown that the tumor suppressor gene lethal (2) giant discs (lgd) is required to prevent ectopic activation of Notch in developmental processes in Drosophila. Here we show that lgd is required in all imaginal disc cells to suppress the activity of the Notch pathway. lgd encodes a member of a poorly characterized protein family present in all animals, which includes a member that is involved in an inheritable form of mental retardation in humans. Our analysis reveals that Lgd is required for endosomal trafficking of Notch and other proteins. In the absence of Lgd, Notch is activated in a ligand-independent manner in probably all imaginal disc cells in an endosomal compartment downstream of the block in hrs mutants.

Deletion of the Coffin–Lowry Syndrome Gene Rsk2 in Mice is Associated With Impaired Spatial Learning and Reduced Control of Exploratory Behavior

Coffin-Lowry Syndrome (CLS) is an X-linked syndromic form of mental retardation associated with skeletal abnormalities. It is caused by mutations of the Rsk2 gene, which encodes a growth factor regulated kinase. Gene deletion studies in mice have shown an essential role for the Rsk2 gene in osteoblast differentiation and function, establishing a causal link between Rsk2 deficiency and skeletal abnormalities of CLS. Although analyses in mice have revealed prominent expression of Rsk2 in brain structures that are essential for learning and memory, evidence at the behavioral level for an involvement of Rsk2 in cognitive function is still lacking. Here, we have examined Rsk2-deficient mice in two extensive batteries of behavioral tests, which were conducted independently in two laboratories in Zurich (Switzerland) and Orsay (France). Despite the known reduction of bone mass, all parameters of motor function were normal, confirming the suitability of Rsk2-deficient mice for behavioral testing. Rsk2-deficient mice showed a mild impairment of spatial working memory, delayed acquisition of a spatial reference memory task and long-term spatial memory deficits. In contrast, associative and recognition memory, as well as the habituation of exploratory activity were normal. Our studies also revealed mild signs of disinhibition in exploratory activity, as well as a difficulty to adapt to new test environments, which likely contributed to the learning impairments displayed by Rsk2-deficient mice. The observed behavioral changes are in line with observations made in other mouse models of human mental retardation and support a role of Rsk2 in cognitive functions.

Shroom4 (Kiaa1202) is an actin‐associated protein implicated in cytoskeletal organization

All animal cells utilize a specialized set of cytoskeletal proteins to determine their overall shape and the organization of their intracellular compartments and organelles. During embryonic development, the dynamic nature of the actin cytoskeleton is critical for virtually all morphogenic events requiring changes in cell shape, migration, adhesion, and division. The behavior of the actin cytoskeleton is modulated by a myriad of accessory proteins. Shroom3 is an actin binding protein that regulates neural tube morphogenesis by eliciting changes in cell shape through a myosin II-dependent pathway. The Shroom-related gene SHROOM4 (formerly called KIAA1202) has also been implicated in neural development, as mutations in this gene are associated with human X-linked mental retardation. To better understand the function of Shrm4 in embryonic development, we have cloned mouse Shroom4 and characterized its protein product in vivo and in vitro. Shroom4 is expressed in a wide range of cell types during mouse development, including vascular endothelium and the polarized epithelium of the neural tube and kidney. In endothelial cells and embryo fibroblasts, endogenous Shroom4 co-distributes with myosin II to a distinct cytoplasmic population of F-actin and ectopic expression of Shroom4 in multiple cell types enhances or induces the formation of this actin-based structure. This localization is mediated, at least in part, by the direct interaction of Shroom4 and F-actin. Our results suggest that Shroom4 is a regulator of cytoskeletal architecture that may play an important role in vertebrate development.

Wnt Gets Dendrites Right

Proper function of the nervous system requires that neurons make appropriate contacts with other neurons through their dendritic arbors, and defects in dendritic structures are associated with mental retardation in humans. Neuronal activity is required for correct outgrowth and branching of dendrites. Recent evidence has shown that wingless or Wnt signaling, which is so important in regulating other aspects of development, is also a crucial regulator of dendritic development. Wayman et al. present a series of experiments that piece together a calcium-dependent signaling pathway that appears to link neuronal activity with transcriptional control of Wnt expression. In cultured rat hippocampal neurons, the authors used siRNA to restrict expression of the γ isoform of calcium/calmodulin-dependent protein kinase I (CaMKIγ) and show that this isoform is specifically required for activity-dependent development of dendrites through its activation of the mitogen-activated protein kinase ERK (extracellular signal-regulated kinase). Furthermore, constitutively active forms of MEK (a protein kinase that acts in the kinase cascade that activates ERK) or CaMKI could replace neuronal activation in stimulating dendrite development. The transcription factor CREB (cyclic AMP response element-binding protein) was confirmed to be activated by this calcium-dependent activation of ERK. A serial analysis of chromatin occupancy (SACO) screen [which combines chromatin immunoprecipitation (ChIP) with a modification of SAGE (serial analysis of gene expression)] was used to identify Wnt-2 as a target of CREB activated in response to neuronal activity. Neuronal activity also stimulated transcription of Wnt-2 in cultured hippocampal slices, and expression of the Wnt antagonist Wif blocked activity-dependent dendritic outgrowth. Together the results of Wayman et al. show a pathway from the NMDA ( N -methyl-D-aspartate) receptor transmitted through CaMK kinase, CamKI, the GTPase Ras, ERK, and CREB that leads to transcriptional control of Wnt. It is possible, the authors propose, that a similar pathway could control Wnt signaling in other developmental contexts. G. A. Wayman, S. Impey, D. Marks, T. Saneyoshi, W. F. Grant, V. Derkach, T. R. Soderling, Activity-dependent dendritic arborization mediated by CaM-kinase I activation and enhanced CREB-dependent transcription of Wnt-2. Neuron 50 , 897-909 (2006). [Online Journal]

Analysis of the in vivo function of the zebrafish fragile X gene family

Fragile X Syndrome is the leading cause of inherited mental retardation in humans. This X-linked disorder results from underexpression of the Fragile X mental retardation related protein(FMR1P) due to expansion and hypermethylation of a CGG trinucleotide repeat in the 5V UTR region of the Fragile X gene(fmr1). Fmr1 has two autosomal homologs, fxr1 and fxr2, which together comprise a family of highly conserved RNAbinding proteins thought to be involved with mRNA transport and translation, although their precise function(s) in development have not been determined. Expression analyses of these three zebrafish genes have been conducted by this laboratory and others. We have begun an analysis of the in vivo role of the Fragile X gene family in early zebrafish development through the use of morpholino(mo) oligonucleotide knockdowns. We are injecting 1–8 cell stage zebrafish embryos with mo-derived anti-sense reagents designed against the translation start sites of the three zebrafish Fragile Xrelated genes. Injected embryos are assayed for gross morphologic defects, as well as changes in organization of the nervous system through detection of axon tracts with anti-acetylated tubulin antibody. The well-described development of the early zebrafish nervous system, along with the ability to study dose-dependent inactivation of these target sequences individually and in combination should be powerful tools to help discern the in vivo function(s) of the Fragile X gene family in development.

Rec8 phosphorylation and recombination promote the step-wise loss of cohesins in meiosis

During meiosis, cohesins--protein complexes that hold sister chromatids together--are lost from chromosomes in a step-wise manner. Loss of cohesins from chromosome arms is necessary for homologous chromosomes to segregate during meiosis I. Retention of cohesins around centromeres until meiosis II is required for the accurate segregation of sister chromatids. Here we show that phosphorylation of the cohesin subunit Rec8 contributes to step-wise cohesin removal. Our data further implicate two other key regulators of meiotic chromosome segregation, the cohesin protector Sgo1 and meiotic recombination in bringing about the step-wise loss of cohesins and thus the establishment of the meiotic chromosome segregation pattern. Understanding the interplay between these processes should provide insight into the events underlying meiotic chromosome mis-segregation, the leading cause of miscarriages and mental retardation in humans.

Metabotropic Receptor-Dependent Long-Term Depression Persists in the Absence of Protein Synthesis in the Mouse Model of Fragile X Syndrome

Fragile X syndrome (FXS), a form of human mental retardation, is caused by loss of function mutations in the fragile X mental retardation gene (FMR1). The protein product of FMR1, fragile X mental retardation protein (FMRP) is an RNA-binding protein and may function as a translational suppressor. Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) in hippocampal area CA1 is a form of synaptic plasticity that relies on dendritic protein synthesis. mGluR-LTD is enhanced in the mouse model of FXS, Fmr1 knockout (KO) mice, suggesting that FMRP negatively regulates translation of proteins required for LTD. Here we examine the synaptic and cellular mechanisms of mGluR-LTD in KO mice and find that mGluR-LTD no longer requires new protein synthesis, in contrast to wild-type (WT) mice. We further show that mGluR-LTD in KO and WT mice is associated with decreases in AMPA receptor (AMPAR) surface expression, indicating a similar postsynaptic expression mechanism. However, like LTD, mGluR-induced decreases in AMPAR surface expression in KO mice persist in protein synthesis inhibitors. These results are consistent with recent findings of elevated protein synthesis rates and synaptic protein levels in Fmr1 KO mice and suggest that these elevated levels of synaptic proteins are available to increase the persistence of LTD without de novo protein synthesis.

Altered organization of cortical interneurons in rats exposed to ethanol during neonatal life

The fetal alcohol syndrome (FAS) is a known cause of mental retardation in humans. Studies based on experimental models of FAS have demonstrated deep alterations of the cerebral cortex. Here, the anatomical organization of cortical interneurons immunoreactive for different calcium binding proteins has been studied in adult rats exposed to alcohol inhalation during the first week of postnatal life. The main finding is represented by an increase of calretinin neurons in ethanol-treated animals compared to controls and by a corresponding decrease of calbindin neurons. The radial distribution of these neurons was also modified in ethanol-treated cases. These changes were evident both in the primary motor and somatosensory area. No significant differences were found in the number and distribution of parvalbumin interneurons. The functional implications of these data and their significance for FAS are discussed.

PQBP‐1 is expressed predominantly in the central nervous system during development

Mutations of PQBP-1 (polyglutamine binding protein-1) have been shown recently to cause human mental retardation accompanied by microcephaly at a high frequency. As a first step towards understanding the molecular basis of this developmental anomaly, we analysed developmental expression of PQBP-1 by in situ hybridization, immunohistochemistry and Western blot analysis. Although it had been shown by Northern blot analysis that PQBP-1 mRNA is expressed in multiple organs in adult mice, our present results revealed that PQBP-1 mRNA and protein are dominantly expressed in the central nervous system (CNS) in embryos and in newborn mice. The mean expression level of PQBP-1 reaches a peak around birth and is down-regulated in adulthood. Furthermore, the expression pattern in the CNS changes remarkably following birth. PQBP-1 mRNA in the cerebral cortex is high in embryos but it rapidly decreases after birth. PQBP-1 mRNA increases in external and internal granular cell layers of the cerebellum from postnatal day 1 (P1) to P5. In addition, expression in the subventricular zone, where neurogenesis occurs, was high from P5 to adulthood. Collectively, these findings suggest that PQBP-1 might be involved in neuronal proliferation and/or maturation. These ideas may be relevant to the insufficient growth of brain structure reported in PQBP-1-linked human mental retardation.

Chemical Biology of Protein Lipidation: Semi‐Synthesis and Structure Elucidation of Prenylated RabGTPases

AbstractFor Abstract see ChemInform Abstract in Full Text.

Cortical Development: New Concepts

Cortical Development: New Concepts

Methyl-CpG binding proteins in the nervous system

Classical methyl-CpG binding proteins contain the conserved DNA binding motif methyl-cytosine binding domain (MBD), which preferentially binds to methylated CpG dinucleotides. These proteins serve as transcriptional repressors, mediating gene silencing via DNA cytosine methylation. Mutations in methyl-CpG binding protein 2 (MeCP2) have been linked to the human mental retardation disorder Rett syndrome, suggesting an important role for methyl-CpG binding proteins in brain development and function. This mini-review summarizes the recent advances in studying the diverse functions of MeCP2 as a prototype for other methyl-CpG binding proteins in the development and function of the vertebrate nervous system.

Chemical biology of protein lipidation: semi-synthesis and structure elucidation of prenylated RabGTPases

Rab/Ypt guanosine triphosphatases (GTPases) represent a family of key membrane traffic regulators in eukaryotic cells. For their function Rab/Ypt proteins require double modification with two covalently bound geranylgeranyl lipid moieties at the C-terminus. Generally, prenylated proteins are very difficult to obtain by recombinant or enzymatic methods. We generated prenylated RabGTPases using a combination of chemical synthesis and protein engineering. This semi-synthesis depends largely on the availability of functionalized prenylated peptides corresponding to the proteins' native structure or modifications. We developed solution phase and solid phase strategies for the generation of peptides corresponding to the prenylated C-terminus of Rab7 GTPase in preparative amounts enabling us to crystallize the mono-prenylated Ypt1:RabGDI complex. The structure of the complex provides a structural basis for the ability of RabGDI to inhibit the release of nucleotide by Rab proteins and a molecular basis for understanding a RabGDI mutant that causes mental retardation in humans.

Long-term changes in glutamatergic synaptic transmission in phenylketonuria

The cellular mechanisms that underlie impaired brain function during phenylketonuria (PKU), the most common biochemical cause of mental retardation in humans, remain unclear. Acute application of L-Phe at concentrations observed in the PKU brain depresses glutamatergic synaptic transmission but does not affect GABA receptor activity in cultured neurons. If these depressant effects of L-Phe take place in the PKU brain, then chronic impairment of the glutamate system, which may contribute to impaired brain function, could be detected as changes in postsynaptic glutamate receptors. This hypothesis was tested by using a combination of liquid chromatography-mass spectrometry, patch-clamp, radioligand binding and western blot approaches in forebrain tissue from heterozygous and homozygous (PKU) Pah(enu2) mice. Brain concentrations of L-Phe were nearly six-fold greater in PKU mice (863.12 +/- 17.96 micromol/kg) than in their heterozygous counterparts (149.32 +/- 10.23 micromol/kg). This concentration is significantly higher than the K(B) of 573 microM for L-Phe to compete for N-methyl-D-aspartate (NMDA) receptors. Receptor binding experiments with [3H]MK-801 showed significant up-regulation of NMDA receptor density in PKU mice. Consistent with the depressant effects of L-Phe, expression of NMDA receptor NR2A and (RS)-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor Glu1 and Glu2/3 subunits was significantly increased, whereas expression of the NR2B subunit was decreased. There was no change in GABA alpha1 subunit expression. Given the role of the glutamatergic system in brain development and function, these changes may, at least in part, explain the brain disorders associated with PKU.

Age- and region-specific imbalances of basal amino acids and monoamine metabolism in limbic regions of female Fmr1 knock-out mice

The Fragile X syndrome, a common form of mental retardation in humans, originates from the loss of expression of the Fragile X mental retardation gene leading to the absence of the encoded Fragile X mental retardation protein 1 (FMRP). A broad pattern of morphological and behavioral abnormalities is well described for affected humans as well as Fmr1 knock-out mice, a transgenic animal model for the human Fragile X syndrome. In the present study, we examined neurochemical differences between female Fmr1 knock-out and wildtype mice with particular focus on neurotransmission. Significant age- and region-specific differences of basal tissue neurotransmitter and metabolite levels measured by high performance liquid chromatography were found. Those differences were more numerous in juvenile animals (postnatal day (PND) 28–31) compared to adults (postnatal day 209–221). In juvenile female knock-out mice, especially aspartate and taurine were increased in cortical regions, striatum, cerebellum, and brainstem. Furthermore, compared to the wildtype animals, the juvenile knock-out mice displayed an increased level of neuronal inhibition in the hippocampus and brainstem reflected by decreased ratios of (aspartate+glutamate)/(taurine+GABA), as well as an increased dopamine (DA) turnover in cortical regions, striatum, and hippocampus. These results provide the first evidence that the lack of FMRP expression in female Fmr1 knock-out mice is accompanied by age-dependent, region-specific alterations in brain amino acids, and monoamine turnover, which might be related to the reported synaptical and behavioural alterations in these animals.

Differences in DNA methylation patterns between humans and chimpanzees

Methylation at CpG dinucleotides is important for gene regulation in mammals [1]. However, it is unknown how methylation patterns change during evolution. Here, we compare methylation patterns between humans and chimpanzees at 36 genes in the brain, the liver and in lymphocytes. We find that the extent of the change in methylation pattern is much more extensive in the brain than in the other tissues. Furthermore, of the 15 CpGs that have significantly changed methylation in the brain, 14 are more methylated in humans than in chimpanzees. This indicates that CpGs might generally be more methylated in human brains than in chimpanzee brains. Despite considerable phenotypic differences, humans and their closest living relatives, the chimpanzees, are on average 98.8% identical in their alignable genomic DNA sequences [2,3]. It is currently unknown which genotypic differences are responsible for the phenotypic differences. One possibility to tackle this question is to compare gene expression patterns between humans and chimpanzees using functional genomic approaches [4–6]. In this respect, it may also be useful to compare methylation patterns in regulatory DNA sequences, as the methylation status can be viewed as a “footprint” of the chromatin structures that are crucial for gene regulation [7,8]. In order to take a first step toward understanding the evolution of methylation patterns, we compared the methylation status of 145 CpGs in the presumed regulatory regions of 36 different genes between humans and chimpanzees in brain, liver and lymphocytes using a recently developed array technique [9–11]. Thereby, genomic DNA is treated with sodium bisulphite such that unmethylated CpGs are amplified as TpGs in the following PCR. For each CpG examined, the arrays contain two oligonucleotides: one complementary to a TpG, resembling a formerly unmethylated CpG and one complementary to a CpG, resembling a formerly methylated CpG. We identified 22 CpGs in which the ratio of the intensities of these two oligonucleotides differed significantly between human and chimpanzee in at least one tissue. By contrast, zero to three differences would be expected due to random experimental and biological variation, as is shown by permutating the species labels for each tissue (see supplemental data for all methodological details). Therefore, the differences between the two species are highly significant, whereas the differences between the individuals of the same species are within the range of the experimental error (data not shown). We also do not observe a strong correlation of methylation levels with age or time post mortem (see supplemental data), Thus, we conclude that most of the observed methylation differences between humans and chimpanzees are neither due to random measurement errors nor due to random or systematic differences in their environment. To exclude trivial genetic causes, we sequenced the region of the 22 CpG sites in the chimpanzee and excluded 4 CpGs that carried a sequence difference between the chimpanzee sequence and the human-based oligonucleotide sequence. The remaining 18 CpGs from 12 genes are shown in Figure 1. Three observations from these experiments are especially noteworthy: First, despite the limited number of CpGs studied, several significant differences in their methylation status can be found between humans and chimpanzees. Second, out of 18 differences, 15 are found between chimpanzee and human brain, whereas only six are found between the other two tissues. Third, 14 of the 15 sites differing in methylation in the brain show a higher degree of methylation in humans. The first observation indicates that — at least in humans and chimpanzees — the methylation status of many CpG sites changes during the course of evolution. The second observation indicates that more CpG sites have changed their methylation status in the brain than in liver or lymphocytes. Notably, DNA methylation seems to be especially important for the brain, as defects in methylation lead to mental retardation in humans [8] and a mouse model for one of these diseases — Rett syndrome — indicates that the symptoms can be caused solely by a defect in postmitotic neurons [12,13]. Our third observation, namely that 14 of 15 CpG sites differently methylated in the brain show a higher degree of methylation in humans, might reflect a general up-methylation of genes in the human brain, rather than several independent, gene-specific methylation changes. Although it is unclear at this point whether this up-methylation directly translates into observable changes in gene expression (supplemental data), it is tempting to speculate that such an upmethylation was important for the evolution of the human brain. However, we cannot exclude that a general tendency towards a lower degree of methylation occurred on the chimpanzee lineage. It is furthermore unclear if the change in methylation patterns is especially pronounced in the human brain or if a rapid change in methylation patterns is typical of brain evolution in many mammals. Further work has to clarify these issues.

Array-Based Comparative Genomic Hybridization for the Genomewide Detection of Submicroscopic Chromosomal Abnormalities

Microdeletions and microduplications, not visible by routine chromosome analysis, are a major cause of human malformation and mental retardation. Novel high-resolution, whole-genome technologies can improve the diagnostic detection rate of these small chromosomal abnormalities. Array-based comparative genomic hybridization allows such a high-resolution screening by hybridizing differentially labeled test and reference DNAs to arrays consisting of thousands of genomic clones. In this study, we tested the diagnostic capacity of this technology using approximately 3,500 flourescent in situ hybridization-verified clones selected to cover the genome with an average of 1 clone per megabase (Mb). The sensitivity and specificity of the technology were tested in normal-versus-normal control experiments and through the screening of patients with known microdeletion syndromes. Subsequently, a series of 20 cytogenetically normal patients with mental retardation and dysmorphisms suggestive of a chromosomal abnormality were analyzed. In this series, three microdeletions and two microduplications were identified and validated. Two of these genomic changes were identified also in one of the parents, indicating that these are large-scale genomic polymorphisms. Deletions and duplications as small as 1 Mb could be reliably detected by our approach. The percentage of false-positive results was reduced to a minimum by use of a dye-swap-replicate analysis, all but eliminating the need for laborious validation experiments and facilitating implementation in a routine diagnostic setting. This high-resolution assay will facilitate the identification of novel genes involved in human mental retardation and/or malformation syndromes and will provide insight into the flexibility and plasticity of the human genome.

Structure of Rab GDP-dissociation inhibitor in complex with prenylated YPT1 GTPase.

Rab/Ypt guanosine triphosphatases (GTPases) represent a family of key membrane traffic regulators in eukaryotic cells whose function is governed by the guanosine diphosphate (GDP) dissociation inhibitor (RabGDI). Using a combination of chemical synthesis and protein engineering, we generated and crystallized the monoprenylated Ypt1:RabGDI complex. The structure of the complex was solved to 1.5 angstrom resolution and provides a structural basis for the ability of RabGDI to inhibit the release of nucleotide by Rab proteins. Isoprenoid binding requires a conformational change that opens a cavity in the hydrophobic core of its domain II. Analysis of the structure provides a molecular basis for understanding a RabGDI mutant that causes mental retardation in humans.

CYFIP/Sra-1 Controls Neuronal Connectivity in Drosophila and Links the Rac1 GTPase Pathway to the Fragile X Protein

Neuronal plasticity requires actin cytoskeleton remodeling and local protein translation in response to extracellular signals. Rho GTPase pathways control actin reorganization, while the fragile X mental retardation protein (FMRP) regulates the synthesis of specific proteins. Mutations affecting either pathway produce neuronal connectivity defects in model organisms and mental retardation in humans. We show that CYFIP, the fly ortholog of vertebrate FMRP interactors CYFIP1 and CYFIP2, is specifically expressed in the nervous system. CYFIP mutations affect axons and synapses, much like mutations in dFMR1 (the Drosophila FMR1 ortholog) and in Rho GTPase dRac1. CYFIP interacts biochemically and genetically with dFMR1 and dRac1. Finally, CYFIP acts as a dRac1 effector that antagonizes FMR1 function, providing a bridge between signal-dependent cytoskeleton remodeling and translation.