The neuronal Arf GAP centaurin α1 modulates dendritic differentiation

Moore, Carlene; Thacker, Erin E.; Larimore, Jennifer L.; Gaston, David C; Underwood, Alison; Kearns, Brian G.; Patterson, Sean I.; Jackson, Trevor; Chapleau, Chris; Pozzo-Miller, Lucas; Theibert, Anne B.

doi:10.1242/jcs.006346

Cited by 56 publications

(54 citation statements)

References 80 publications

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“…Proper trafficking between the various endomembrane compartments is crucial for proper furrow formation, and this trafficking also seems to be important in the maintenance of neuronal morphology and function (Kennedy and Ehlers, 2006). An effector of COPI vesicle formation, the GTPase activating protein Arf1 GAP, is essential for dendritic growth and outbranching (Moore et al, 2007). FMRP is also involved in dendritic growth and branching, suggesting a possible connection between the two pathways.…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis reveals CCT is a target of Fragile X mental retardation protein regulation in Drosophila

Monzo

Dowd

Minden

et al. 2010

Developmental Biology

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Fragile X mental retardation protein (FMRP) is an RNA-binding protein that is required for the translational regulation of specific target mRNAs. Loss of FMRP causes Fragile X Syndrome (FXS), the most common form of inherited mental retardation in humans. Understanding the basis for FXS has been limited because few in vivo targets of FMRP have been identified and mechanisms for how FMRP regulates physiological targets is unclear. We have previously demonstrated that Drosophila FMRP (dFMRP) is required in early embryos for cleavage furrow formation. In an effort to identify new targets of dFMRP-dependent regulation and new effectors of cleavage furrow formation, we used two-dimensional difference gel electrophoresis and mass spectrometry to identify proteins that are misexpressed in dfmr1 mutant embryos. Of the 28 proteins identified, we have identified three subunits of the Chaperonin containing TCP-1 (CCT) complex as new direct targets of dFMRP-dependent regulation. Furthermore, we found that the septin Peanut, a known effector of cleavage, is a likely conserved substrate of fly CCT and is mislocalized in both cct and in dfmr1 mutant embryos. Based on these results we propose that dFMRP-dependent regulation of CCT subunits is required for cleavage furrow formation and that at least one of its substrates is affected in dfmr1- embryos suggesting dFMRP-dependent regulation of CCT contributes to the cleavage furrow formation phenotype.

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Section: Discussionmentioning

confidence: 99%

Proteomic analysis reveals CCT is a target of Fragile X mental retardation protein regulation in Drosophila

Monzo

Dowd

Minden

et al. 2010

Developmental Biology

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“…After 6–8 days in vitro (div), slice cultures were bombarded with Au particles accelerated by ∼100psi He from a distance of 2cm using a hand-held gene gun (Helios, Bio-Rad) with a modified nozzle, as previously described (Alonso et al ., 2004). The success rate of co-transfection of the same neuron with two cDNA plasmids using the gene-gun has been demonstrated to be >90% (Boda et al ., 2004; Moore et al ., 2007), reducing the likelihood of analyzing eYFP-positive, MeCP2-negative neurons. After 48hrs or 96hrs post-transfection, hippocampal slice cultures were fixed by immersion in 4% paraformaldehyde in 100mM phosphate buffer (overnight at 4°C), and washed in PBS.…”

Section: Methodsmentioning

confidence: 99%

Dendritic spine pathologies in hippocampal pyramidal neurons from Rett syndrome brain and after expression of Rett-associated MECP2 mutations

Chapleau

Calfa

Lane

et al. 2009

Neurobiology of Disease

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Rett syndrome (RTT) is an X chromosome-linked neurodevelopmental disorder associated with the characteristic neuropathology of dendritic spines common in diseases presenting with mental retardation (MR). Here, we present the first quantitative analyses of dendritic spine density in postmortem brain tissue from female RTT individuals, which revealed that hippocampal CA1 pyramidal neurons have lower spine density than age-matched non-MR female control individuals. The majority of RTT individuals carry mutations in MECP2, the gene coding for a methylated DNA-binding transcriptional regulator. While altered synaptic transmission and plasticity has been demonstrated in Mecp2-deficient mouse models of RTT, observations regarding dendritic spine density and morphology have produced varied results. We investigated the consequences of MeCP2 dysfunction on dendritic spine structure by overexpressing (∼twofold) MeCP2-GFP constructs encoding either the wildtype (WT) protein, or missense mutations commonly found in RTT individuals. Pyramidal neurons within hippocampal slice cultures transfected with either WT or mutant MECP2 (either R106W or T158M) showed a significant reduction in total spine density after 48hrs of expression. Interestingly, spine density in neurons expressing WT MECP2 for 96hrs was comparable to that in control neurons, while neurons expressing mutant MECP2 continued to have lower spines density than controls after 96hrs of expression. Knockdown of endogenous Mecp2 with a specific small hairpin interference RNA (shRNA) also reduced dendritic spine density, but only after 96hrs of expression. On the other hand, the consequences of manipulating MeCP2 levels for dendritic complexity in CA3 pyramidal neurons were only minor. Together, these results demonstrate reduced dendritic spine density in hippocampal pyramidal neurons from RTT patients, a distinct dendritic phenotype also found in neurons expressing RTT-associated MECP2 mutations or after shRNA-mediated endogenous Mecp2 knockdown, suggesting that this phenotype represent a cell-autonomous consequence of MeCP2 dysfunction.

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“…6C). The members of the ARF family of small GTPases were previously reported to affect dendritic branching and spine formation (Herná ndez- Deviez et al 2002;Moore et al 2007).…”

Section: Pqbp1 Affects the As Of Mrnas In Neuronsmentioning

confidence: 99%

PQBP1, a factor linked to intellectual disability, affects alternative splicing associated with neurite outgrowth

et al. 2013

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Polyglutamine-binding protein 1 (PQBP1) is a highly conserved protein associated with neurodegenerative disorders. Here, we identify PQBP1 as an alternative messenger RNA (mRNA) splicing (AS) effector capable of influencing splicing of multiple mRNA targets. PQBP1 is associated with many splicing factors, including the key U2 small nuclear ribonucleoprotein (snRNP) component SF3B1 (subunit 1 of the splicing factor 3B [SF3B] protein complex). Loss of functional PQBP1 reduced SF3B1 substrate mRNA association and led to significant changes in AS patterns. Depletion of PQBP1 in primary mouse neurons reduced dendritic outgrowth and altered AS of mRNAs enriched for functions in neuron projection development. Disease-linked PQBP1 mutants were deficient in splicing factor associations and could not complement neurite outgrowth defects. Our results indicate that PQBP1 can affect the AS of multiple mRNAs and indicate specific affected targets whose splice site determination may contribute to the disease phenotype in PQBP1-linked neurological disorders.

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The neuronal Arf GAP centaurin α1 modulates dendritic differentiation

Cited by 56 publications

References 80 publications

Proteomic analysis reveals CCT is a target of Fragile X mental retardation protein regulation in Drosophila

Proteomic analysis reveals CCT is a target of Fragile X mental retardation protein regulation in Drosophila

Dendritic spine pathologies in hippocampal pyramidal neurons from Rett syndrome brain and after expression of Rett-associated MECP2 mutations

PQBP1, a factor linked to intellectual disability, affects alternative splicing associated with neurite outgrowth

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