The EphA4 Receptor Regulates Neuronal Morphology through SPAR-Mediated Inactivation of Rap GTPases

Richter, Melanie; Murai, Keith K.; Bourgin, Caroline; Pak, Daniel T.S.; Pasquale, Elena B.

doi:10.1523/jneurosci.2746-07.2007

Cited by 73 publications

(65 citation statements)

References 66 publications

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“…Activation of EphA4 receptors is necessary for remodeling of CA1 dendritic spines in processes of synaptic plasticity in the adult brain [45][46][47], and EphA4 null mice have hippocampal distorted spines, confirming that EphA4 is required to maintain normal spine architecture in vivo [14,48]. An early decrease in EphA4 receptor protein was found in the hippocampus of hAβPP swe-ind mice, which may account for the impairment in synaptic plasticity in this brain region particularly vulnerable to degeneration in AD.…”

Section: Discussionmentioning

confidence: 76%

Early Changes in Hippocampal Eph Receptors Precede the Onset of Memory Decline in Mouse Models of Alzheimer's Disease

Simón

Maturana

Ricobaraza

et al. 2009

JAD

102

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Abstract. Synapse loss occurs early in Alzheimer's disease (AD) and is considered the best pathological correlate of cognitive decline. Ephrins and Eph receptors are involved in regulation of excitatory neurotransmission and play a role in cytoskeleton remodeling. We asked whether alterations in Eph receptors could underlie cognitive impairment in an AD mouse model overexpressing human amyloid-β protein precursor (hAβPP) with familial mutations (hAβPP swe-ind mice). We found that EphA4 and EphB2 receptors were reduced in the hippocampus before the development of impaired object recognition and spatial memory. Similar results were obtained in another line of transgenic AβPP mice, Tg2576. A reduction in Eph receptor levels was also found in postmortem hippocampal tissue from patients with incipient AD. At the time of onset of memory decline in hAβPP swe-ind mice, no change in surface expression of AMPA or NMDA receptor subunits was apparent, but we found changes in Eph-receptor downstream signaling, in particular a decrease in membrane-associated phospho-cofilin levels that may cause cytoskeletal changes and disrupted synaptic activity. Consistent with this finding, Eph receptor activation in cell culture increased phospho-cofilin levels. The results suggest that alterations in Eph receptors may play a role in synaptic dysfunction in the hippocampus leading to cognitive impairment in a model of AD.

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Section: Discussionmentioning

confidence: 76%

Early Changes in Hippocampal Eph Receptors Precede the Onset of Memory Decline in Mouse Models of Alzheimer's Disease

Simón

Maturana

Ricobaraza

et al. 2009

JAD

102

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“…EphB enhances synapse development via its interaction with NMDA receptors (13), whereas EphA4, which is mainly expressed in the adult hippocampus, acts as a negative regulator of neurotransmission and hippocampal synaptic plasticity (14). EphA4 activation by its ligands, ephrins, triggers forward signaling (12) that leads to the retraction of dendritic spines via cyclin-dependent kinase 5 (Cdk5)-dependent RhoA activation and reduced cell adhesion (15)(16)(17). EphA4 also causes the removal of synaptic and surface AMPA receptors during homeostatic plasticity (18,19).…”

mentioning

confidence: 99%

Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer’s disease

Hung

Huang

et al. 2014

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

167

180

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Alzheimer's disease (AD), characterized by cognitive decline, has emerged as a disease of synaptic failure. The present study reveals an unanticipated role of erythropoietin-producing hepatocellular A4 (EphA4) in mediating hippocampal synaptic dysfunctions in AD and demonstrates that blockade of the ligand-binding domain of EphA4 reverses synaptic impairment in AD mouse models. Enhanced EphA4 signaling was observed in the hippocampus of amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD, whereas soluble amyloid-β oligomers (Aβ), which contribute to synaptic loss in AD, induced EphA4 activation in rat hippocampal slices. EphA4 depletion in the CA1 region or interference with EphA4 function reversed the suppression of hippocampal long-term potentiation in APP/PS1 transgenic mice, suggesting that the postsynaptic EphA4 is responsible for mediating synaptic plasticity impairment in AD. Importantly, we identified a smallmolecule rhynchophylline as a novel EphA4 inhibitor based on molecular docking studies. Rhynchophylline effectively blocked the EphA4-dependent signaling in hippocampal neurons, and oral administration of rhynchophylline reduced the EphA4 activity effectively in the hippocampus of APP/PS1 transgenic mice. More importantly, rhynchophylline administration restored the impaired long-term potentiation in transgenic mouse models of AD. These findings reveal a previously unidentified role of EphA4 in mediating AD-associated synaptic dysfunctions, suggesting that it is a new therapeutic target for this disease.Abeta | receptor tyrosine kinase | ephrin | drug discovery

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“…Since an interaction of the Sipa1l1 PDZ domain with Epha4 has already been reported (Richter et al, 2007), we analyzed the interaction of Sipa1l3 and Epha4. To this end, we overexpressed various Sipa1l3 constructs that encoded different sets of protein interaction domains in Cos7 cells and incubated those with the P2 fraction of mouse brain homogenate.…”

Section: Sipa1l3 Interacts With Epha4mentioning

confidence: 99%

“…This interaction promotes phosphorylation of Sipa1l1 and an inactivation of the small GTPases Rap1 and Rap2 (Richter et al, 2007). Ephrin receptor tyrosine kinases are generally involved in cell recognition, adhesion, axonal pathfinding, growth cone mobility and/or morphology and cataract formation (Huot, 2004;Pasquale, 2005).…”

Section: Introductionmentioning

confidence: 99%

An Epha4/Sipa1l3/Wnt pathway regulates eye development and lens maturation

et al. 2016

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The signal-induced proliferation-associated family of proteins comprises four members, SIPA1 and SIPA1L1-3. Mutations of the human SIPA1L3 gene result in congenital cataracts. In Xenopus, loss of Sipa1l3 function led to a severe eye phenotype that was distinguished by smaller eyes and lenses including lens fiber cell maturation defects. We found a direct interaction between Sipa1l3 and Epha4, building a functional platform for proper ocular development. Epha4 deficiency phenocopied loss of Sipa1l3 and rescue experiments demonstrated that Epha4 acts upstream of Sipa1l3 during eye development, with both Sipa1l3 and Epha4 required for early eye specification. The ocular phenotype, upon loss of either Epha4 or Sipa1l3, was partially mediated by rax. We demonstrate that canonical Wnt signaling is inhibited downstream of Epha4 and Sipa1l3 during normal eye development. Depletion of either Sipa1l3 or Epha4 resulted in an upregulation of axin2 expression, a direct Wnt/β-catenin target gene. In line with this, Sipa1l3 or Epha4 depletion could be rescued by blocking Wnt/β-catenin or activating non-canonical Wnt signaling. We therefore conclude that this pathomechanism prevents proper eye development and maturation of lens fiber cells, resulting in congenital cataracts.

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The EphA4 Receptor Regulates Neuronal Morphology through SPAR-Mediated Inactivation of Rap GTPases

Cited by 73 publications

References 66 publications

Early Changes in Hippocampal Eph Receptors Precede the Onset of Memory Decline in Mouse Models of Alzheimer's Disease

Early Changes in Hippocampal Eph Receptors Precede the Onset of Memory Decline in Mouse Models of Alzheimer's Disease

Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer’s disease

An Epha4/Sipa1l3/Wnt pathway regulates eye development and lens maturation

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