The<i>Drosophila</i>FMRP and LARK RNA-Binding Proteins Function Together to Regulate Eye Development and Circadian Behavior

Sofola, Oyinkan; Sundram, Vasudha; Ng, Fanny S.; Kleyner, Yelena; Morales, Joannella; Botas, Juan; Jackson, F. Rob; Nelson, David L.

doi:10.1523/jneurosci.2786-08.2008

Cited by 32 publications

(34 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…LARK is a known clock output factor, and when overexpressed causes arrhythmic locomotor activity. Accordingly, the double heterozygous mutant for dFmr1 and Lark revealed improvements in these defects (Sofola et al 2008). FMRP and its cytoplasmic interactor CYFIP1, also known as specific RAC-1 activated protein (SRA-1), (Kobayashi et al 1998;Schenck et al 2003) control in an activity-dependent manner actin remodeling and local protein synthesis (Napoli et al 2008;Galy et al 2011;De Rubeis et al 2013;Zhao et al 2013).…”

Section: Dfmr1 Mutant Flies Have Abnormal Circadian Rhythmsmentioning

confidence: 99%

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

2014

View full text Add to dashboard Cite

The Fragile X syndrome (FXS) is the most frequent form of inherited mental disability and is considered a monogenic cause of autism spectrum disorder. FXS is caused by a triplet expansion that inhibits the expression of the FMR1 gene. The gene product, the Fragile X Mental Retardation Protein (FMRP), regulates mRNA metabolism in brain and nonneuronal cells. During brain development, FMRP controls the expression of key molecules involved in receptor signaling, cytoskeleton remodeling, protein synthesis and, ultimately, spine morphology. Symptoms associated with FXS include neurodevelopmental delay, cognitive impairment, anxiety, hyperactivity, and autistic-like behavior. Twenty years ago the first Fmr1 KO mouse to study FXS was generated, and several years later other key models including the mutant Drosophila melanogaster, dFmr1, have further helped the understanding of the cellular and molecular causes behind this complex syndrome. Here, we review to which extent these biological models are affected by the absence of FMRP, pointing out the similarities with the observed human dysfunction. Additionally, we discuss several potential treatments under study in animal models that are able to partially revert some of the FXS abnormalities.

show abstract

Section: Dfmr1 Mutant Flies Have Abnormal Circadian Rhythmsmentioning

confidence: 99%

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

2014

View full text Add to dashboard Cite

show abstract

“…It has a widespread role in translation, mRNA stability and trafficking. Flies lacking dFMRP also have disturbed circadian rhythms presumably due to alterations in clock output [82]. dFMRP and LARK appear to function together and, indeed, common target transcripts of dFMRP and LARK regulation have been identified.…”

Section: Mrna Decaymentioning

confidence: 99%

“…LARK also interacts with dFMRP, the Drosophila orthologue of Fragile X mental retardation protein [82]. Loss of FMRP causes the most common heritable form of mental retardation in mammals and also leads to altered behavioral rhythmicity [83].…”

Section: Mrna Decaymentioning

confidence: 99%

Spotlight on post-transcriptional control in the circadian system

Staiger

Köster

2010

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

An endogenous timing mechanism, the circadian clock, causes rhythmic expression of a considerable fraction of the genome of most organisms to optimally align physiology and behavior with their environment. Circadian clocks are self-sustained oscillators primarily based on transcriptional feedback loops and post-translational modification of clock proteins. It is increasingly becoming clear that regulation at the RNA level strongly impacts the cellular circadian transcriptome and proteome as well as the oscillator mechanism itself. This review focuses on posttranscriptional events, discussing RNA-binding proteins that, by influencing the timing of pre-mRNA splicing, polyadenylation and RNA decay, shape rhythmic expression profiles. Furthermore, recent findings on the contribution of microRNAs to orchestrating circadian rhythms are summarized.

show abstract

“…We first examined synapse connectivity in the central brain, based on well-established dfmr1 phenotypes. dfmr1 null mutants exhibit strikingly abnormal circadian rhythm patterns, with a complete loss of rhythmicity in the absence of environmental entrainment (Bushey et al, 2009;Dockendorff et al, 2002;Inoue et al, 2002;Sofola et al, 2008). Although Fmr1 knockout mice show only mild impairments, the Fmr1/Fxr2 double knockout is likewise entirely arrhythmic (Zhang et al, 2008).…”

Section: Only Fmr1 Restores Brain Circuit Synaptic Architecturementioning

confidence: 99%

Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

Coffee

Tessier

Woodruff

et al. 2010

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

SUMMARYFragile X syndrome (FXS), resulting solely from the loss of function of the human fragile X mental retardation 1 (hFMR1) gene, is the most common heritable cause of mental retardation and autism disorders, with syndromic defects also in non-neuronal tissues. In addition, the human genome encodes two closely related hFMR1 paralogs: hFXR1 and hFXR2. The Drosophila genome, by contrast, encodes a single dFMR1 gene with close sequence homology to all three human genes. Drosophila that lack the dFMR1 gene (dfmr1 null mutants) recapitulate FXS-associated molecular, cellular and behavioral phenotypes, suggesting that FMR1 function has been conserved, albeit with specific functions possibly sub-served by the expanded human gene family. To test evolutionary conservation, we used tissue-targeted transgenic expression of all three human genes in the Drosophila disease model to investigate function at (1) molecular, (2) neuronal and (3) non-neuronal levels. In neurons, dfmr1 null mutants exhibit elevated protein levels that alter the central brain and neuromuscular junction (NMJ) synaptic architecture, including an increase in synapse area, branching and bouton numbers. Importantly, hFMR1 can, comparably to dFMR1, fully rescue both the molecular and cellular defects in neurons, whereas hFXR1 and hFXR2 provide absolutely no rescue. For non-neuronal requirements, we assayed male fecundity and testes function. dfmr1 null mutants are effectively sterile owing to disruption of the 9+2 microtubule organization in the sperm tail. Importantly, all three human genes fully and equally rescue mutant fecundity and spermatogenesis defects. These results indicate that FMR1 gene function is evolutionarily conserved in neural mechanisms and cannot be compensated by either FXR1 or FXR2, but that all three proteins can substitute for each other in non-neuronal requirements. We conclude that FMR1 has a neural-specific function that is distinct from its paralogs, and that the unique FMR1 function is responsible for regulating neuronal protein expression and synaptic connectivity.Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

show abstract

TheDrosophilaFMRP and LARK RNA-Binding Proteins Function Together to Regulate Eye Development and Circadian Behavior

Cited by 32 publications

References 47 publications

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

Spotlight on post-transcriptional control in the circadian system

Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

Contact Info

Product

Resources

About