Cyclin E Constrains Cdk5 Activity to Regulate Synaptic Plasticity and Memory Formation

Odajima, Junko; Wills, Zachary P.; Ndassa, Yasmine; Terunuma, Miho; Kretschmannova, Karla; Deeb, Tarek Z.; Geng, Yan; Gawrzak, Sylwia; Quadros, Isabel M.; Newman, Jennifer L.; Das, Manjusri; Jecrois, Marie; Yu, Qunyan; Li, Na; Bienvenu, Frédéric; Moss, Stephen J.; Greenberg, Michael E.; Marto, Jarrod A.; Siciński, Piotr

doi:10.1016/j.devcel.2011.08.009

Cited by 107 publications

(115 citation statements)

References 50 publications

(68 reference statements)

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“…The Cdk2-cyclin E complex is critical for G1/S transition of the cell cycle and DNA synthesis (Tsai et al, 1993). Recent studies have shown that cyclin E is also highly expressed in adult brain where it forms a complex with Cdk5 (Odajima et al, 2011). Interestingly, instead of activating Cdk5, the binding of cyclin E inactivates Cdk5 and sequesters it away from its normal activators p35 and p39 (Odajima et al, 2011).…”

Section: Cyclin Ementioning

confidence: 99%

“…Recent studies have shown that cyclin E is also highly expressed in adult brain where it forms a complex with Cdk5 (Odajima et al, 2011). Interestingly, instead of activating Cdk5, the binding of cyclin E inactivates Cdk5 and sequesters it away from its normal activators p35 and p39 (Odajima et al, 2011). Moreover, cyclin-E-mediated sequestering of Cdk5 promotes dendritic growth, synaptic plasticity and memory formation in transgenic animal models, suggesting that cyclin-Emediated inhibition of Cdk5 is physiologically relevant (Fig.…”

Section: Cyclin Ementioning

confidence: 99%

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Cdk5 activity in the brain – multiple paths of regulation

Shah

Lahiri

2014

Journal of Cell Science

169

126

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Cyclin dependent kinase-5 (Cdk5), a family member of the cyclindependent kinases, plays a pivotal role in the central nervous system. During embryogenesis, Cdk5 is indispensable for brain development and, in the adult brain, it is essential for numerous neuronal processes, including higher cognitive functions such as learning and memory formation. However, Cdk5 activity becomes deregulated in several neurological disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, which leads to neurotoxicity. Therefore, precise control over Cdk5 activity is essential for its physiological functions. This Commentary covers the various mechanisms of Cdk5 regulation, including several recently identified protein activators and inhibitors of Cdk5 that control its activity in normal and diseased brains. We also discuss the autoregulatory activity of Cdk5 and its regulation at the transcriptional, post-transcriptional and post-translational levels. We finally highlight physiological and pathological roles of Cdk5 in the brain. Specific modulation of these protein regulators is expected to provide alternative strategies for the development of effective therapeutic interventions that are triggered by deregulation of Cdk5.

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Section: Cyclin Ementioning

confidence: 99%

Section: Cyclin Ementioning

confidence: 99%

Cdk5 activity in the brain – multiple paths of regulation

Shah

Lahiri

2014

Journal of Cell Science

169

126

View full text Add to dashboard Cite

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“…For example, Drosophila E2F is required for transfer of cytoplasm from nurse cells to oocytes, and for the establishment of oocyte dorsal-ventral polarity (Myster et al, 2000). In postmitotic mammalian neurons, constitutively expressed CycE binds to and inhibits Cdk5 to control synaptic plasticity and memory formation (Odajima et al, 2011). Activation of Cdk5 in adipocytes as a result of high fat-induced obesity also leads to PPAR phosphorylation and deregulated expression of insulin-sensitizing genes independently of cyclins (Choi et al, 2010).…”

Section: F36mentioning

confidence: 99%

Cyclin E controlsDrosophilafemale germline stem cell maintenance independently of its role in proliferation by modulating responsiveness to niche signals

Ables

Drummond‐Barbosa

2013

Development

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SUMMARYStem cells must proliferate while maintaining 'stemness'; however, much remains to be learned about how factors that control the division of stem cells influence their identity. Multiple stem cell types display cell cycles with short G1 phases, thought to minimize susceptibility to differentiation factors. Drosophila female germline stem cells (GSCs) have short G1 and long G2 phases, and dietdependent systemic factors often modulate G2. We previously observed that Cyclin E (CycE), a known G1/S regulator, is atypically expressed in GSCs during G2/M; however, it remained unclear whether CycE has cell cycle-independent roles in GSCs or whether it acts exclusively by modulating the cell cycle. In this study, we detected CycE activity during G2/M, reflecting its altered expression pattern, and showed that CycE and its canonical partner, Cyclin-dependent kinase 2 (Cdk2), are required not only for GSC proliferation, but also for GSC maintenance. In genetic mosaics, CycE-and Cdk2-deficient GSCs are rapidly lost from the niche, remain arrested in a G1-like state, and undergo excessive growth and incomplete differentiation. However, we found that CycE controls GSC maintenance independently of its role in the cell cycle; GSCs harboring specific hypomorphic CycE mutations are not efficiently maintained despite normal proliferation rates. Finally, CycE-deficient GSCs have an impaired response to niche bone morphogenetic protein signals that are required for GSC self-renewal, suggesting that CycE modulates niche-GSC communication. Taken together, these results show unequivocally that the roles of CycE/Cdk2 in GSC division cycle regulation and GSC maintenance are separable, and thus potentially involve distinct sets of phosphorylation targets.

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“…We have recently described that Cdk5 physically interacts with and phosphorylates SynIII at a unique phosphorylation site (Ser 404 ) that is crucial for the regulation of radial migration of pyramidal neurons in the developing neocortex (Perlini et al, 2015). SynIII and Cdk5 are coexpressed at perinatal ages in the cortex, but thereafter their expression patterns diverge (Ferreira et al, 2000;Odajima et al, 2011;Perlini et al, 2015). Before addressing the role of Cdk5 phosphorylation of SynIII, we checked the distribution of SynIII and p35, the neurospecific Cdk5 activator, in WT cortical neurons at 3 and 14 DIV.…”

Section: A Novel Cdk5 Phosphorylation Site On Syniii Regulates Its Fumentioning

confidence: 99%

Phosphorylation by PKA and Cdk5 Mediates the Early Effects of Synapsin III in Neuronal Morphological Maturation

et al. 2015

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Synapsin III (SynIII) is a neuron-specific phosphoprotein that plays a unique role in neuronal development. SynIII is phosphorylated by cAMP-dependent protein kinase (PKA) at a highly conserved phosphorylation site and by cyclin-dependent kinase-5 (Cdk5) at a newly described site. Although SynIII is known to be involved in axon elongation in vitro, the role of its phosphorylation by PKA and Cdk5 in the modulation of this process is unknown. We expressed either wild-type (WT) or phosphorylation-site mutants of SynIII in primary SynIII knock-out (KO) mouse neurons at early stages of in vitro development. Whereas the neurite elongation phenotype of SynIII KO neurons was fully rescued by the expression of WT SynIII, the expression of nonphosphorylatable and pseudo-phosphorylated PKA mutants was ineffective. Also, the nonphosphorylatable Cdk5 mutant was unable to rescue the neurite elongation phenotype of SynIII KO neurons. By contrast, the pseudo-phosphorylated mutant rescued the delay in neuronal maturation and axonal elongation, revealing a Cdk5-dependent regulation of SynIII function. Interestingly, SynIII KO neurons also exhibited decreased survival that was fully rescued by the expression of WT SynIII, but not by its phosphorylation mutants, and was associated with increased activated caspase3 and altered tropomyosin receptor kinase B isoform expression. These results indicate that PKA and Cdk5 phosphorylation is required for the physiological action of SynIII on axon specification and neurite outgrowth and that the expression of a functional SynIII is crucial for cell survival.

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Cyclin E Constrains Cdk5 Activity to Regulate Synaptic Plasticity and Memory Formation

Cited by 107 publications

References 50 publications

Cdk5 activity in the brain – multiple paths of regulation

Cdk5 activity in the brain – multiple paths of regulation

Cyclin E controlsDrosophilafemale germline stem cell maintenance independently of its role in proliferation by modulating responsiveness to niche signals

Phosphorylation by PKA and Cdk5 Mediates the Early Effects of Synapsin III in Neuronal Morphological Maturation

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