The Guanine Nucleotide Exchange Factor (GEF) Asef2 Promotes Dendritic Spine Formation via Rac Activation and Spinophilin-dependent Targeting

Evans, J. Corey; Robinson, Cristina M.; Shi, Mingjian; Webb, Donna J.

doi:10.1074/jbc.m114.605543

Cited by 27 publications

(25 citation statements)

References 78 publications

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“…Spinophilin modulates dendritic spine density and regulates LTD [17, 37–39]. Spinophilin is known to associate with and modulate the function of multiple synaptic proteins [19, 26, 39–42].…”

Section: Discussionmentioning

confidence: 99%

Mechanisms and Consequences of Dopamine Depletion-Induced Attenuation of the Spinophilin/Neurofilament Medium Interaction

et al. 2017

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Signaling changes that occur in the striatum following the loss of dopamine neurons in the Parkinson disease (PD) are poorly understood. While increases in the activity of kinases and decreases in the activity of phosphatases have been observed, the specific consequences of these changes are less well understood. Phosphatases, such as protein phosphatase 1 (PP1), are highly promiscuous and obtain substrate selectivity via targeting proteins. Spinophilin is the major PP1-targeting protein enriched in the postsynaptic density of striatal dendritic spines. Spinophilin association with PP1 is increased concurrent with decreases in PP1 activity in an animal model of PD. Using proteomic-based approaches, we observed dopamine depletion-induced decreases in spinophilin binding to multiple protein classes in the striatum. Specifically, there was a decrease in the association of spinophilin with neurofilament medium (NF-M) in dopamine-depleted striatum. Using a heterologous cell line, we determined that spinophilin binding to NF-M required overexpression of the catalytic subunit of protein kinase A and was decreased by cyclin-dependent protein kinase 5. Functionally, we demonstrate that spinophilin can decrease NF-M phosphorylation. Our data determine mechanisms that regulate, and putative consequences of, pathological changes in the association of spinophilin with NF-M that are observed in animal models of PD.

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Section: Discussionmentioning

confidence: 99%

Mechanisms and Consequences of Dopamine Depletion-Induced Attenuation of the Spinophilin/Neurofilament Medium Interaction

et al. 2017

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“…A closely related homolog of Ephexin5, Ephexin1 displays GEF specificity that is regulated by its phosphorylation state. Similarly to Ephexin5, Ephexin1 has been shown to target RhoA, but is also capable of activating Cdc42 and Rac1 (Shamah et al, 2001; Sahin et al, 2005), both of which enhance spine density (Tashiro et al, 2000; Wiens et al, 2005; Wegner et al, 2008; Kim et al, 2013; Ueda et al, 2013; Dhar et al, 2014; Raynaud et al, 2014; Evans et al, 2015; Jaudon et al, 2015; Kim et al, 2015; Valdez et al, 2016). Phosphorylation of Ephexin1 by Src kinase, however, causes a shift in Ephexin1 affinity away from Rac1 and Cdc42 towards RhoA, a switch which mediates EphA4-dependent growth cone collapse through RhoA activation (Shamah et al, 2001; Sahin et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Several small GTPases have been characterized as enhancers of spine density, especially Cdc42 (Tashiro et al, 2000; Wegner et al, 2008; Kim et al, 2013; Jaudon et al, 2015) and Rac1 (Tashiro et al, 2000; Penzes et al, 2001; Penzes et al, 2003; Tolias et al, 2007; Bacon et al, 2013; Ueda et al, 2013; Dhar et al, 2014; Raynaud et al, 2014; Evans et al, 2015; Jaudon et al, 2015; Kim et al, 2015; Valdez et al, 2016); others have been shown to inhibit spine density, in particular Ras (Yang et al, 2013; Lee et al, 2016) and RhoA (Tashiro et al, 2000; Margolis et al, 2010; Alder et al, 2013; Kim et al, 2015). Furthermore, modulators of activity for Ras (Pham and Rotin, 2001), Cdc42 (Hayakawa et al, 2008; Yamaguchi et al, 2008), and RhoA (Margolis et al, 2010; Lin et al, 2011; Papadimitriou et al, 2012) have been shown to be degraded by the proteasome, as well as Rac1 (Torrino et al, 2011; Zhao et al, 2013) and RhoA themselves (Wang et al, 2003; Cheng et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

A dual role for the RhoGEF Ephexin5 in regulation of dendritic spine outgrowth

Hamilton

Lambert

Parajuli

et al. 2017

Molecular and Cellular Neuroscience

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The outgrowth of new dendritic spines is closely linked to the formation of new synapses, and is thought to be a vital component of the experience-dependent circuit plasticity that supports learning. Here, we examined the role of the RhoGEF Ephexin5 in driving activity-dependent spine outgrowth. We found that reducing Ephexin5 levels increased spine outgrowth, and increasing Ephexin5 levels decreased spine outgrowth in a GEF-dependent manner, suggesting that Ephexin5 acts as an inhibitor of spine outgrowth. Notably, we found that increased neural activity led to a proteasome-dependent reduction in the levels of Ephexin5 in neuronal dendrites, which could facilitate the enhanced spine outgrowth observed following increased neural activity. Surprisingly, we also found that Ephexin5-GFP levels were elevated on the dendrite at sites of future new spines, prior to new spine outgrowth. Moreover, lowering neuronal Ephexin5 levels inhibited new spine outgrowth in response to both global increases in neural activity and local glutamatergic stimulation of the dendrite, suggesting that Ephexin5 is necessary for activity-dependent spine outgrowth. Our data support a model in which Ephexin5 serves a dual role in spinogenesis, acting both as a brake on overall spine outgrowth and as a necessary component in the site-specific formation of new spines.

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“…Similarly, in a remarkable in vivo study in non-heat-stressed C. elegans, stimulation of the worms' thermo-sensory neurons activated HSF1 in distal tissues (the pharyngeal muscles) (Tatum et al 2015). Rho family GTPases like Rac 1 also activate HSF1 (Han et al 2001;Gungor et al 2014) and play a role in formation of the synaptic spine cytoskeleton (Evans et al 2015). Glycogen synthase kinase-3 (GSK3) inhibition promotes activation of HSF1 by AKT activation (Bijur and Jope 2000), and is associated with synaptic functional integrity and improved cognitive ability (King et al 2014).…”

Section: Pathways Of Hsf1 Activationmentioning

confidence: 93%

The central role of heat shock factor 1 in synaptic fidelity and memory consolidation

Hooper

Durham

Török

et al. 2016

Cell Stress and Chaperones

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Networks of neuronal synapses are the fundamental basis for making and retaining memory. Reduced synapse number and quality correlates with loss of memory in dementia. Heat shock factor 1 (HSF1), the major transcription factor regulating expression of heat shock genes, plays a central role in proteostasis, in establishing and sustaining synaptic fidelity and function, and in memory consolidation. Support for this thesis is based on these observations: (1) heat shock induces improvements in synapse integrity and memory consolidation; (2) synaptic depolarization activates HSF1; (3) activation of HSF1 alone (independent of the canonical heat shock response) augments formation of essential synaptic elementsneuroligands, vesicle transport, synaptic scaffolding proteins, lipid rafts, synaptic spines, and axodendritic synapses; (4) HSF1 coalesces and activates memory receptors in the postsynaptic dendritic spine; (5) huntingtin or α-synuclein accumulation lowers HSF1 while HSF1 lowers huntingtin and α-synuclein aggregation-a potential vicious cycle; and (6) HSF1 agonists (including physical activity) can improve cognitive function in dementia models. Thus, via direct gene expression of synaptic elements, production of HSPs that assure high protein fidelity, and activation of other neuroprotective signaling pathways, HSF1 agonists could provide breakthrough therapy for dementia-associated disease.

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The Guanine Nucleotide Exchange Factor (GEF) Asef2 Promotes Dendritic Spine Formation via Rac Activation and Spinophilin-dependent Targeting

Cited by 27 publications

References 78 publications

Mechanisms and Consequences of Dopamine Depletion-Induced Attenuation of the Spinophilin/Neurofilament Medium Interaction

Mechanisms and Consequences of Dopamine Depletion-Induced Attenuation of the Spinophilin/Neurofilament Medium Interaction

A dual role for the RhoGEF Ephexin5 in regulation of dendritic spine outgrowth

The central role of heat shock factor 1 in synaptic fidelity and memory consolidation

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