Fragile X protein controls the efficacy of mRNA transport in Drosophila neurons

Estes, Patricia S.; O’Shea, Michele; Clasen, Sara J; Zarnescu, Daniela C.

doi:10.1016/j.mcn.2008.06.012

Cited by 78 publications

(68 citation statements)

References 25 publications

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“…2C) at 40-60 min after group I mGluR stimulation. This agrees with a previous finding that in dfmr mutant neurons, CG9293 mRNA exhibits less directional movement (35). CaMKIIα has been shown to have other associated mRNPs, possibly modifying directionality (36).…”

Section: Discussionsupporting

confidence: 93%

Altered mRNA transport, docking, and protein translation in neurons lacking fragile X mental retardation protein

Kao¹,

Aldridge

Weiler³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

126

109

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Fragile X syndrome is caused by the absence of functional fragile X mental retardation protein (FMRP), an RNA binding protein. The molecular mechanism of aberrant protein synthesis in fmr1 KO mice is closely associated with the role of FMRP in mRNA transport, delivery, and local protein synthesis. We show that GFP-labeled Fmr1 and CaMKIIα mRNAs undergo decelerated motion at 0-40 min after group I mGluR stimulation, and later recover at 40-60 min. Then we investigate targeting of mRNAs associated with FMRP after neuronal stimulation. We find that FMRP is synthesized closely adjacent to stimulated mGluR5 receptors. Moreover, in WT neurons, CaMKIIα mRNA can be delivered and translated in dendritic spines within 10 min in response to group I mGluR stimulation, whereas KO neurons fail to show this response. These data suggest that FMRP can mediate spatial mRNA delivery for local protein synthesis in response to synaptic stimulation.fragile X syndrome | dendritic mRNA targeting | local translation F ragile X syndrome (FXS) is the most common form of inherited mental retardation and is caused by the loss of function of the FMR1 gene, which encodes fragile X mental retardation protein (FMRP) (1). FXS affects 1 in 4,000 males and 1 in 6,000 females on average and is characterized by hyperactivity, attention deficits, autistic-like behaviors, and seizures (2). Dendritic spine morphology in the cerebral cortex of FXS patients and in the fmr1 KO mouse model shows more immature long thin spines than mature stubby, mushroom-shaped spines (3). Furthermore, group I mGluR-dependent long-term depression in the hippocampus is exaggerated in the fmr1 KO model (4). These findings suggest that FMRP functions in synaptic development and plasticity.Activity-dependent local translation is a fundamental mechanism underlying synaptic plasticity (5, 6). Inhibition of protein synthesis attenuates specific types of long-term plasticity (7,8). Morphological changes in dendritic spines can be blocked by protein synthesis inhibitors (9). In the fmr1 KO model, it has been shown that aberrant synthesis of individual proteins such as CaMKIIα, PSD-95, and MAP1b, upon group I mGluR stimulation, is associated with defective long-term plasticity (10-12). Here we have studied specific molecular mechanisms to elucidate aberrant localized translation in the fmr1 KO model. The molecular basis of FMRP's role in translation-dependent plasticity remains unclear despite extensive study. FMRP is a ribosome-associated RNA binding protein with selective affinity (13,14). Upon neuronal stimulation, FMRP may regulate protein levels by mediating translational regulation and mRNA trafficking (11, 15). FMRP, mRNA, and other RNA binding proteins can form ribonucleoprotein (RNP) or granule structures and couple with motor proteins to be transported in dendrites (16-18). Dendritic transport of FMRP and associated mRNAs, such as Fmr1, CaMKIIα, and MAP1b, are regulated by group I mGluR signaling (15, 19). It is not yet fully understood how and when mRNA is delivered to th...

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Section: Discussionsupporting

confidence: 93%

Altered mRNA transport, docking, and protein translation in neurons lacking fragile X mental retardation protein

Kao¹,

Aldridge

Weiler³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

126

109

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“…We designed a genetic screen on the basis of the idea that the amelioration (or suppression) of the sev-dfmr1 induced rough-eye phenotype could occur when one copy of a gene required for FMR1-mediated translational control is removed, as previously shown for ago1, me31B, and tral ( Jin et al 2004b;Barbee et al 2006). Secondary assays indicative of direct interactions with dFMR1 (described in later sections) were used to identify/rule out alternative mechanisms of phenotypic suppression (Estes et al 2008).…”

Section: Resultsmentioning

confidence: 99%

Genetic Modifiers ofdFMR1Encode RNA Granule Components in Drosophila

Cziko¹,

McCann

Howlett³

et al. 2009

Genetics

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Mechanisms of neuronal mRNA localization and translation are of considerable biological interest. Spatially regulated mRNA translation contributes to cell-fate decisions and axon guidance during development, as well as to long-term synaptic plasticity in adulthood. The Fragile-X Mental Retardation protein (FMRP/dFMR1) is one of the best-studied neuronal translational control molecules and here we describe the identification and early characterization of proteins likely to function in the dFMR1 pathway. Induction of the dFMR1 in sevenless-expressing cells of the Drosophila eye causes a disorganized (rough) eye through a mechanism that requires residues necessary for dFMR1/FMRP's translational repressor function. Several mutations in dco, orb2, pAbp, rm62, and smD3 genes dominantly suppress the sev-dfmr1 rough-eye phenotype, suggesting that they are required for dFMR1-mediated processes. The encoded proteins localize to dFMR1-containing neuronal mRNPs in neurites of cultured neurons, and/or have an effect on dendritic branching predicted for bona fide neuronal translational repressors. Genetic mosaic analyses indicate that dco, orb2, rm62, smD3, and dfmr1 are dispensable for translational repression of hid, a microRNA target gene, known to be repressed in wing discs by the bantam miRNA. Thus, the encoded proteins may function as miRNA-and/or mRNA-specific translational regulators in vivo.

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“…Taken together, the data indicate that although dFmr1 and Atx2 function together with Me31B in the translational regulation of the dendritic CaMKII reporter mRNA, dFmr1 is dispensable but Atx2 broadly necessary for the presence of Me31B foci that represent likely sites of RNA regulation in neurons. Although these observations also indicate that dFmr1 is not essential for the dendritic transport of the majority of Me31B-containing mRNPs in vivo, it remains possible that dFmr1 contributes to transport dynamics or for trafficking of a subset of RNAs (65)(66)(67).…”

Section: Regulation Of Camkii Expression By Dfmr1 and Other Micrornmentioning

confidence: 86%

FMRP and Ataxin-2 function together in long-term olfactory habituation and neuronal translational control

Sudhakaran

Hillebrand

Dervan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

115

147

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Fragile X mental retardation protein (FMRP) and Ataxin-2 (Atx2) are triplet expansion disease-and stress granule-associated proteins implicated in neuronal translational control and microRNA function. We show that Drosophila FMRP (dFMR1) is required for long-term olfactory habituation (LTH), a phenomenon dependent on Atx2-dependent potentiation of inhibitory transmission from local interneurons (LNs) to projection neurons (PNs) in the antennal lobe. dFMR1 is also required for LTH-associated depression of odor-evoked calcium transients in PNs. Strong transdominant genetic interactions among dFMR1, atx2, the deadbox helicase me31B, and argonaute1 (ago1) mutants, as well as coimmunoprecitation of dFMR1 with Atx2, indicate that dFMR1 and Atx2 function together in a microRNA-dependent process necessary for LTH. Consistently, PN or LN knockdown of dFMR1, Atx2, Me31B, or the miRNA-pathway protein GW182 increases expression of a Ca2+/calmodulin-dependent protein kinase II (CaMKII) translational reporter. Moreover, brain immunoprecipitates of dFMR1 and Atx2 proteins include CaMKII mRNA, indicating respective physical interactions with this mRNA. Because CaMKII is necessary for LTH, these data indicate that fragile X mental retardation protein and Atx2 act via at least one common target RNA for memory-associated long-term synaptic plasticity. The observed requirement in LNs and PNs supports an emerging view that both presynaptic and postsynaptic translation are necessary for long-term synaptic plasticity. However, whereas Atx2 is necessary for the integrity of dendritic and somatic Me31B-containing particles, dFmr1 is not. Together, these data indicate that dFmr1 and Atx2 function in long-term but not short-term memory, regulating translation of at least some common presynaptic and postsynaptic target mRNAs in the same cells.synapse plasticity | olfactory memory | neural circuits | neurological disease

show abstract

Fragile X protein controls the efficacy of mRNA transport in Drosophila neurons

Cited by 78 publications

References 25 publications

Altered mRNA transport, docking, and protein translation in neurons lacking fragile X mental retardation protein

Altered mRNA transport, docking, and protein translation in neurons lacking fragile X mental retardation protein

Genetic Modifiers ofdFMR1Encode RNA Granule Components in Drosophila

FMRP and Ataxin-2 function together in long-term olfactory habituation and neuronal translational control

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