Mental retardation genes in drosophila: New approaches to understanding and treating developmental brain disorders

Restifo, Linda L.

doi:10.1002/mrdd.20083

Cited by 31 publications

(27 citation statements)

References 120 publications

(145 reference statements)

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“…Drosophila express the dfmr1 protein, dfmrp, in the central nervous system and specifically in mushroom bodies, key neural structures in learning and memory (Schenck, Van de Bor et al 2002). The dfmr1 mutant, an FX fly model, has an altered mushroom body structure which contributes to the FX memory phenotype (Michel, Kraft et al 2004;Pan, Zhang et al 2004;Restifo 2005). One example of an altered FX fly memory phenotype comes from assessment using conditioned courtship behavior, a model for memory in Drosophila (McBride, Giuliani et al 1999).…”

Section: Fragile X Flymentioning

confidence: 99%

The cyclic AMP phenotype of fragile X and autism

Kelley

Bhattacharyya

Lahvis

et al. 2008

Neuroscience & Biobehavioral Reviews

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Cyclic AMP (cAMP) is a second messenger involved in many processes including mnemonic processing and anxiety. Memory deficits and anxiety are noted in the phenotype of fragile X (FX), the most common heritable cause of mental retardation and autism. Here we review reported observations of altered cAMP cascade function in FX and autism. Cyclic AMP is a potentially useful biochemical marker to distinguish autism comorbid with FX from autism per se and the cAMP cascade may be a viable therapeutic target for both FX and autism.

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Section: Fragile X Flymentioning

confidence: 99%

The cyclic AMP phenotype of fragile X and autism

Kelley

Bhattacharyya

Lahvis

et al. 2008

Neuroscience & Biobehavioral Reviews

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“…In this study, we generated a mutant fly model of PQBP1-linked MR in which a transposon repressed the Drosophila homolog of PQBP1 (dPQBP1) gene expression and investigated their learning and memory by using the strength of Drosophila models (for review, see Restifo, 2005). Unexpectedly, we found that PQBP1 regulates aversive olfactory learning at PNs.…”

Section: Introductionmentioning

confidence: 99%

DrosophilaPQBP1 Regulates Learning Acquisition at Projection Neurons in Aversive Olfactory Conditioning

Tamura

Horiuchi²,

Chen³

et al. 2010

J. Neurosci.

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Polyglutamine tract-binding protein-1 (PQBP1) is involved in the transcription-splicing coupling, and its mutations cause a group of human mental retardation syndromes. We generated a fly model in which the Drosophila homolog of PQBP1 (dPQBP1) is repressed by insertion of piggyBac. In classical odor conditioning, learning acquisition was significantly impaired in homozygous piggyBac-inserted flies, whereas the following memory retention was completely normal. Mushroom bodies (MBs) and antennal lobes were morphologically normal in dPQBP1-mutant flies. Projection neurons (PNs) were not reduced in number and their fiber connections were not changed, whereas gene expressions including NMDA receptor subunit 1 (NR1) were decreased in PNs. Targeted double-stranded RNAmediated silencing of dPQBP1 in PNs, but not in MBs, similarly disrupted learning acquisition. NR1 overexpression in PNs rescued the learning disturbance of dPQBP1 mutants. HDAC (histone deacetylase) inhibitors, SAHA (suberoylanilide hydroxamic acid) and PBA (phenylbutyrate), that upregulated NR1 partially rescued the learning disturbance. Collectively, these findings identify dPQBP1 as a novel gene regulating learning acquisition at PNs.

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“…We were specifically motivated by studies demonstrating defective growth cone motility (Kim and Wu, 1996) and electrophysiology (Rohrbough et al, 2003) of brain neurons from learning or memory mutants. More generally, because of phylogenetic conservation, the Drosophila genetic model system shows great promise in the study of neurological disorders (Bier, 2005), particularly mental retardation (Inlow and Restifo, 2004;Restifo, 2005).…”

Section: Introductionmentioning

confidence: 99%

Phenotypes ofDrosophilaBrain Neurons in Primary Culture Reveal a Role for Fascin in Neurite Shape and Trajectory

Kraft¹,

Escobar²,

Narro³

et al. 2006

J. Neurosci.

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Subtle cellular phenotypes in the CNS may evade detection by routine histopathology. Here, we demonstrate the value of primary culture for revealing genetically determined neuronal phenotypes at high resolution. Gamma neurons of Drosophila melanogaster mushroom bodies (MBs) are remodeled during metamorphosis under the control of the steroid hormone 20-hydroxyecdysone (20E). In vitro, wild-type ␥ neurons retain characteristic morphogenetic features, notably a single axon-like dominant primary process and an arbor of short dendrite-like processes, as determined with microtubule-polarity markers. We found three distinct genetically determined phenotypes of cultured neurons from grossly normal brains, suggesting that subtle in vivo attributes are unmasked and amplified in vitro. First, the neurite outgrowth response to 20E is sexually dimorphic, being much greater in female than in male ␥ neurons. Second, the ␥ neuron-specific "naked runt" phenotype results from transgenic insertion of an MB-specific promoter. Third, the recessive, panneuronal "filagree" phenotype maps to singed, which encodes the actin-bundling protein fascin. Fascin deficiency does not impair the 20E response, but neurites fail to maintain their normal, nearly straight trajectory, instead forming curls and hooks. This is accompanied by abnormally distributed filamentous actin. This is the first demonstration of fascin function in neuronal morphogenesis. Our findings, along with the regulation of human Fascin1 (OMIM 602689) by CREB (cAMP response element-binding protein) binding protein, suggest FSCN1 as a candidate gene for developmental brain disorders. We developed an automated method of computing neurite curvature and classifying neurons based on curvature phenotype. This will facilitate detection of genetic and pharmacological modifiers of neuronal defects resulting from fascin deficiency.

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Mental retardation genes in drosophila: New approaches to understanding and treating developmental brain disorders

Cited by 31 publications

References 120 publications

The cyclic AMP phenotype of fragile X and autism

The cyclic AMP phenotype of fragile X and autism

DrosophilaPQBP1 Regulates Learning Acquisition at Projection Neurons in Aversive Olfactory Conditioning

Phenotypes ofDrosophilaBrain Neurons in Primary Culture Reveal a Role for Fascin in Neurite Shape and Trajectory

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