ARF6 and EFA6A Regulate the Development and Maintenance of Dendritic Spines

Choi, Su-Jeong; Ko, Jaewon; Lee, Jae-Ran; Lee, Hyun Woo; Kim, Karam; Chung, Hye Sun; Kim, Hyun; Kim, Eunjoon

doi:10.1523/jneurosci.4182-05.2006

Cited by 93 publications

(132 citation statements)

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“…18 As suggested by the presence of a PDZ-binding motif, the IQSEC2 protein is anchored at PSD via its interaction with PSD-95, which also interacts with NMDA receptors. 19,20 At the PSD, the IQSEC2 protein activates the ARF6 substrate that has been shown to regulate the formation and maintenance of dendritic spines, 21 the branching of axons and dendrites, 22,23 exocytosis and endocytosis of synaptic vesicles, 24,25 and receptor internalization. 25,26 Disease-related variants directly modify the DNA sequence or can influence mRNA splicing leading to the lack of the correct gene product or to the formation of truncated proteins.…”

Section: Discussionmentioning

confidence: 99%

A novel splicing mutation in the IQSEC2 gene that modulates the phenotype severity in a family with intellectual disability

et al. 2016

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The IQSEC2 gene is located on chromosome Xp11.22 and encodes a guanine nucleotide exchange factor for the ADPribosylation factor family of small GTPases. This gene is known to have a significant role in cytoskeletal organization, dendritic spine morphology and synaptic organization. Variants in IQSEC2 cause moderate to severe intellectual disability in males and a variable phenotype in females because this gene escapes from X-chromosome inactivation. Here we report on the first splicing variant in IQSEC2 (g.88032_88033del; NG_021296.1) that co-segregates in a family diagnosed with an X-linked form of ID. In a percentage of the cells, the variant activates an intraexonic splice acceptor site that abolishes 26 amino acids from the highly conserved PH domain of IQSEC2 and creates a premature stop codon 36 amino acids later in exon 13. Interestingly, the percentage of aberrant splicing seems to correlate with the severity of the disease in each patient. The impact of this variant in the target tissue is unknown, but we can hypothesize that these differences may be related to the amount of abnormal IQSEC2 transcript. To our knowledge, we are reporting a novel mechanism of IQSEC2 involvement in ID. Variants that affect splicing are related to many genetic diseases and the understanding of their role in disease expands potential opportunities for gene therapy. Modulation of aberrant splicing transcripts can become a potent therapeutic approach for many of these diseases.

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Section: Discussionmentioning

confidence: 99%

A novel splicing mutation in the IQSEC2 gene that modulates the phenotype severity in a family with intellectual disability

et al. 2016

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“…A further study to determine the role MMP-9 plays in chronic hypoperfusion would be to induce this damage model in MMP-9 knockout mice. IQSEC1(mRNA) and subsequent Arf6 (protein) are highly expressed in the brain [65]. This molecule is involved in actin dynamics, lipid modification and membrane trafficking, specifically axonal transport after damage [66,67].…”

Section: Discussionmentioning

confidence: 99%

Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil–DNA glycosylase impair learning in a mouse model of vascular cognitive impairment

Jadavji

Farr

Lips

et al. 2015

Behavioural Brain Research

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(2015) Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil-DNA glycosylase impair learning in a mouse model of vascular cognitive impairment. Behavioural Brain Research, 283 . pp. 215-226. ISSN 1872-7549 Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/32983/9/UNG_FADD_20140826_manuscript_final.pdf Copyright and reuse:The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions. This article is made available under the Creative Commons Attribution Non-commercial No Derivatives licence and may be reused according to the conditions of the licence. For more details see: http://creativecommons.org/licenses/by-nc-nd/2.5/ A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.uk Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil-DNA glycosylase impair learning in a mouse model of vascular cognitive impairment. ABSTRACTDietary deficiencies in folic acid result in elevated levels of plasma homocysteine, which has been associated with the development of dementia and other neurodegenerative disorders.Previously, we have shown that elevated levels of plasma homocysteine in mice deficient for a DNA repair enzyme, uracil-DNA glycosylase (UNG), result in neurodegeneration. The goal of this study was to evaluate how deficiencies in folic acid and UNG along with elevated levels of homocysteine affect vascular cognitive impairment, via chronic hypoperfusion in an animal model. Ung+/+ and Ung−/− mice were placed on either control (CD) or folic acid deficient (FADD) diets. Six weeks later, the mice either underwent implantation of microcoils around both common carotid arteries. Post-operatively, behavioral tests began at 3-weeks, angiography was measured after 5-weeks using MRI to assess vasculature and at completion of study plasma and brain tissue was collected for analysis. Learning impairments in the Morris water maze (MWM) were observed only in hypoperfused Ung−/− FADD mice and these mice had significantly higher plasma homocysteine concentrations. Interestingly, Ung+/+ FADD produced significant remodeling of the basilar artery and arterial vasculature. Increased expression of GFAP was observed in the dentate gyrus of Ung−/− hypoperfused and FADD sham mice. Chronic hypoperfusion resulted in increased cortical MMP-9 protein levels of FADD hypoperfused mice regardless of genotypes. These results suggest that elevated levels of homocysteine only, as a result of dietary folic acid deficiency, don't lead to memory impairments and neurobiochemical changes. Rather a combination of either chronic hypoperfusion o...

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“…The efficiency of shRNAs was tested on protein levels of HA-tagged rat PAK1 or rat ARF6 in HEK293T cells (data not shown). Both PAK1 and ARF6 targeting sequences have been already reported (13,23). The fidelity of all constructs was verified by sequencing.…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, it was seen that ARF6 regulates early axonal and dendritic growth and branching (10,11). Besides its involvement in early neuronal morphogenesis, ARF6 is known to play a role in later stages of neuronal development, and recent studies have reported that ARF6 affects dendritic spine formation and causes morphological changes (11)(12)(13). These studies, however, presented contradictory results regarding the role of ARF6 in spine development.…”

mentioning

confidence: 99%

“…Miyazaki et al (12) found that a constitutively active mutant of ARF6 (ARF6-Q67L) displayed a severe spine reduction in mature hippocampal neurons (21 days in vitro (DIV 21)), whereas a dominant negative mutant of ARF6 (ARF6-T27N) resulted in a substantial increase in spine density. Choi et al (13), however, showed that activation of ARF6 by overexpression of a fast cycling mutant of ARF6 (ARF6-T157A) increases the spine density in developing neurons (DIV 11), whereas a knockdown of ARF6 resulted in decreased spine formation. Although several explanations regarding this controversy have been suggested, it is still unclear whether ARF6 activation plays a positive or negative role in spine development.…”

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confidence: 99%

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ADP-ribosylation Factor 6 (ARF6) Bidirectionally Regulates Dendritic Spine Formation Depending on Neuronal Maturation and Activity

Kim

Lee

Park

et al. 2015

Journal of Biological Chemistry

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Background:Conflicting results regarding the role of ARF6 in dendritic spine development have not been answered. Results: ARF6-mediated Rac1 or RhoA activation via PLD pathway either positively or negatively regulates spine formation. Conclusion:The key factor underlying conversion of the ARF6 effect during development is neuronal activity. Significance: Activity dependence of ARF6-mediated spine formation may play a role in structural plasticity of mature neurons.

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ARF6 and EFA6A Regulate the Development and Maintenance of Dendritic Spines

Cited by 93 publications

References 50 publications

A novel splicing mutation in the IQSEC2 gene that modulates the phenotype severity in a family with intellectual disability

A novel splicing mutation in the IQSEC2 gene that modulates the phenotype severity in a family with intellectual disability

Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil–DNA glycosylase impair learning in a mouse model of vascular cognitive impairment

ADP-ribosylation Factor 6 (ARF6) Bidirectionally Regulates Dendritic Spine Formation Depending on Neuronal Maturation and Activity

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