Activation of Aurora-A Is Essential for Neuronal Migration via Modulation of Microtubule Organization

Takitoh, Takako; Kumamoto, Kenzo; Wang, Chen Chi; Sato, Makoto; Toba, Shiori; Wynshaw‐Boris, Anthony; Hirotsune, Shinji

doi:10.1523/jneurosci.5664-11.2012

Cited by 25 publications

(29 citation statements)

References 51 publications

(73 reference statements)

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“…Dredrup et al further observed that p35 knock-out mice display behavioral phenotypes reminiscent of ADHD [20]. In addition, as noted before, Cdk5 directs tangential migration of interneurons by activating ErbB4/PI3K pathway, dysfunction of which is repeated linked to neurodevelopmental disorders such as autism and schizophrenia [64]. The authors indeed show that loss in Cdk5 activity in p35 knockout mice causes permanent reduction in the final number of specific types of interneurons, which in turn may alter neuronal circuit formation, thereby increasing the risk of neurodevelopmental disorders.…”

Section: Reduced Activity and Hyperactivity Of Cdk5 Are Each Potentiamentioning

confidence: 95%

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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: Reduced Activity and Hyperactivity Of Cdk5 Are Each Potentiamentioning

confidence: 95%

“…In turn, Aurora A phosphorylates Ndel1 at S251, resulting in MT remodeling and neuronal migration (Fig. 3) [64]. Depletion of Cdk5 reduced the centrosomal targeting of Cdk5RAP2, phosphorylation of Aurora A at T288, and that of Ndel1 at S251, which resulted in impaired neuronal movement.…”

Section: Role Of Cdk5 In Neuronal Migrationmentioning

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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“…; Takitoh et al . ). Therefore, growth arrest signals may provide additional functions beyond cell cycle regulation for some cell cycle‐related proteins.…”

Section: Linking Mechanisms Of Cell Cycle Exit and Neuronal Migrationmentioning

confidence: 97%

Extra‐cell cycle regulatory functions of cyclin‐dependent kinases (CDK) and CDK inhibitor proteins contribute to brain development and neurological disorders

2013

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In developing brains, neural progenitors exhibit cell cycle-dependent nuclear movement within the ventricular zone [interkinetic nuclear migration (INM)] and actively proliferate to produce daughter progenitors and/or neurons, whereas newly generated neurons exit from the cell cycle and begin pial surface-directed migration and maturation. Dysregulation of the balance between the proliferation and the cell cycle exit in neural progenitors is one of the major causes of microcephaly (small brain). Recent studies indicate that cell cycle machinery influences not only the proliferation but also INM in neural progenitors. Furthermore, several cell cycle-related proteins, including p27kip1, p57kip2, Cdk5, and Rb, regulate the migration of neurons in the postmitotic state, suggesting that the growth arrest confers dual functions on cell cycle regulators. Consistently, several types of microcephaly occur in conjunction with neuronal migration disorders, such as periventricular heterotopia and lissencephaly. However, cell cycle re-entry by disturbance of growth arrest in mature neurons is thought to trigger neuronal cell death in Alzheimer's disease. In this review, we introduce the cell cycle protein-mediated regulation of two types of nuclear movement, INM and neuronal migration, during cerebral cortical development, and discuss the roles of growth arrest in cortical development and neurological disorders.

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“…To address this question, we injected TdTomato 19 into embryos to visualize neural networks at E16.520. In particular, we have focused on neural networks in amygdala (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Expression vectors were introduced into fetal brains by an in utero electroporation-mediated gene transfer method20. Briefly, pregnant mice were deeply anesthetized on E16.5, and the uterine horns were exposed.…”

Section: Methodsmentioning

confidence: 99%

Post-natal treatment by a blood-brain-barrier permeable calpain inhibitor, SNJ1945 rescued defective function in lissencephaly

Toba

Tamura

Kumamoto

et al. 2013

Sci Rep

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Toward a therapeutic intervention of lissencephaly, we applied a novel calpain inhibitor, SNJ1945. Peri-natal or post-natal treatment with SNJ1945 rescued defective neuronal migration in Lis1+/− mice, impaired behavioral performance and improvement of 18F-FDG uptake. Furthermore, SNJ1945 improved the neural circuit formation and retrograde transport of NFG in Lis1+/− mice. Thus, SNJ1945 is a potential drug for the treatment of human lissencephaly patients.

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Activation of Aurora-A Is Essential for Neuronal Migration via Modulation of Microtubule Organization

Cited by 25 publications

References 51 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

Extra‐cell cycle regulatory functions of cyclin‐dependent kinases (CDK) and CDK inhibitor proteins contribute to brain development and neurological disorders

Post-natal treatment by a blood-brain-barrier permeable calpain inhibitor, SNJ1945 rescued defective function in lissencephaly

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