Phosphorylation of CRMP2 is involved in proper bifurcation of the apical dendrite of hippocampal CA1 pyramidal neurons

Niisato, Emi; Nagai, Jun; Yamashita, Naoya; Nakamura, Fumio; Goshima, Yoshio; Ohshima, Toshio

doi:10.1002/dneu.22048

Cited by 36 publications

(30 citation statements)

References 38 publications

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“…2). Importantly, Cdk5-mediated CRMP2 phosphorylation at S522 is essential for proper organization of the dendritic field and the precise bifurcation of apical dendrites of CA1 pyramidal neurons in vivo [42, 45]. …”

Section: Role Of Cdk5 In Mt Dynamicsmentioning

confidence: 99%

A Tale of the Good and Bad: Remodeling of the Microtubule Network in the Brain by Cdk5

Shah

Lahiri

2016

Mol Neurobiol

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Cdk5, a cyclin dependent kinase family member, is a global orchestrator of neuronal cytoskeletal dynamics. During embryogenesis, Cdk5 is indispensable for brain development. In adults, it is essential for numerous neuronal processes, including higher cognitive functions such as learning and memory formation, drug addiction, pain signaling and long term behavior changes through long term potentiation and long term depression, all of which rely on rapid alterations in the cytoskeleton. Cdk5 activity becomes deregulated in various brain disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, attention-deficit hyperactivity disorder, epilepsy, schizophrenia and ischemic stroke; these all result in profound remodeling of the neuronal cytoskeleton. This Commentary specifically focuses on the pleiotropic contribution of Cdk5 in regulating neuronal microtubule remodeling. Because the vast majority of the physiological substrates of Cdk5 are associated with the neuronal cytoskeleton, our emphasis is on the Cdk5 substrates, such as CRMP2, stathmin, drebrin, dixdc1, axin, GKAP, kinesin-5, tau and PSD-95, that have allowed to unravel the molecular mechanisms through which Cdk5 exerts its divergent roles in regulating neuronal microtubule dynamics, both in healthy and disease states.

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Section: Role Of Cdk5 In Mt Dynamicsmentioning

confidence: 99%

A Tale of the Good and Bad: Remodeling of the Microtubule Network in the Brain by Cdk5

Shah

Lahiri

2016

Mol Neurobiol

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“…Along those same lines, dephosphorylation by the protein phosphatases PP2A and PP1 promotes neurite outgrowth (Zhu et al, 2010; Astle et al, 2011). Elegant studies by the Ohshima and Goshima groups suggest that changes in the phosphorylation state of CRMP2 may allow for dynamic regulation of outgrowth and branching patterns, as phosphorylation by Cdk5 is necessary for proper bifurcation of CA1 apical dendrites as well as organization of dendritic fields (Yamashita et al, 2012; Niisato et al, 2013). In fact, the ability of CRMP2 to coordinate axon guidance/growth cone collapse by Sema3A relies on phosphorylation (Arimura et al, 2005; Uchida et al, 2005, 2009).…”

Section: Introductionmentioning

confidence: 99%

The functionalized amino acid (S)-Lacosamide subverts CRMP2-mediated tubulin polymerization to prevent constitutive and activity-dependent increase in neurite outgrowth

Wilson

Moutal

Melemedjian

et al. 2014

Front. Cell. Neurosci.

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Activity-dependent neurite outgrowth is a highly complex, regulated process with important implications for neuronal circuit remodeling in development as well as in seizure-induced sprouting in epilepsy. Recent work has linked outgrowth to collapsin response mediator protein 2 (CRMP2), an intracellular phosphoprotein originally identified as axon guidance and growth cone collapse protein. The neurite outgrowth promoting function of CRMP2 is regulated by its phosphorylation state. In this study, depolarization (potassium chloride)-driven activity increased the level of active CRMP2 by decreasing its phosphorylation by GSK3β via a reduction in priming by Cdk5. To determine the contribution of CRMP2 in activity-driven neurite outgrowth, we screened a limited set of compounds for their ability to reduce neurite outgrowth but not modify voltage-gated sodium channel (VGSC) biophysical properties. This led to the identification of (S)-lacosamide ((S)-LCM), a stereoisomer of the clinically used antiepileptic drug (R)-LCM (Vimpat®), as a novel tool for preferentially targeting CRMP2-mediated neurite outgrowth. Whereas (S)-LCM was ineffective in targeting VGSCs, the presumptive pharmacological targets of (R)-LCM, (S)-LCM was more efficient than (R)-LCM in subverting neurite outgrowth. Biomolecular interaction analyses revealed that (S)-LCM bound to wildtype CRMP2 with low micromolar affinity, similar to (R)-LCM. Through the use of this novel tool, the activity-dependent increase in neurite outgrowth observed following depolarization was characterized to be reliant on CRMP2 function. Knockdown of CRMP2 by siRNA in cortical neurons resulted in reduced CRMP2-dependent neurite outgrowth; incubation with (S)-LCM phenocopied this effect. Other CRMP2-mediated processes were unaffected. (S)-LCM subverted neurite outgrowth not by affecting the canonical CRMP2-tubulin association but rather by impairing the ability of CRMP2 to promote tubulin polymerization, events that are perfunctory for neurite outgrowth. Taken together, these results suggest that changes in the phosphorylation state of CRMP2 are a major contributing factor in activity-dependent regulation of neurite outgrowth.

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“…Several knockout mice studies have begun to reveal the in vivo roles of CRMPs in neuronal development and function (Charrier et al, 2006; Yamashita et al, 2006, 2007, 2011, 2012; Su et al, 2007; Quach et al, 2008; Niisato et al, 2012a,b). CRMP1 regulates neuronal cell migration, dendritic spine development, and synaptic plasticity in vivo (Charrier et al, 2006; Yamashita et al, 2006, 2007; Su et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Mice lacking collapsin response mediator protein 1 manifest hyperactivity, impaired learning and memory, and impaired prepulse inhibition

Yamashita

Takahashi

Takao

et al. 2013

Front. Behav. Neurosci.

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Collapsin response mediator protein 1 (CRMP1) is one of the CRMP family members that are involved in various aspects of neuronal development such as axonal guidance and neuronal migration. Here we provide evidence that crmp1−/− mice exhibited behavioral abnormalities related to schizophrenia. The crmp1−/− mice exhibited hyperactivity and/or impaired emotional behavioral phenotype. These mice also exhibited impaired context-dependent memory and long-term memory retention. Furthermore, crmp1−/− mice exhibited decreased prepulse inhibition, and this phenotype was rescued by administration of chlorpromazine, a typical antipsychotic drug. In addition, in vivo microdialysis revealed that the methamphetamine-induced release of dopamine in prefrontal cortex was exaggerated in crmp1−/− mice, suggesting that enhanced mesocortical dopaminergic transmission contributes to their hyperactivity phenotype. These observations suggest that impairment of CRMP1 function may be involved in the pathogenesis of schizophrenia. We propose that crmp1−/− mouse may model endophenotypes present in this neuropsychiatric disorder.

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Phosphorylation of CRMP2 is involved in proper bifurcation of the apical dendrite of hippocampal CA1 pyramidal neurons

Cited by 36 publications

References 38 publications

A Tale of the Good and Bad: Remodeling of the Microtubule Network in the Brain by Cdk5

A Tale of the Good and Bad: Remodeling of the Microtubule Network in the Brain by Cdk5

The functionalized amino acid (S)-Lacosamide subverts CRMP2-mediated tubulin polymerization to prevent constitutive and activity-dependent increase in neurite outgrowth

Mice lacking collapsin response mediator protein 1 manifest hyperactivity, impaired learning and memory, and impaired prepulse inhibition

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