Role of cyclin-dependent kinase 5 and its activator P35 in local axon and growth cone stabilization

Hahn, Christian; Kleinholz, Heike; Koester, Michael P.; Grieser, S.; Thelen, Karsten; Pollerberg, G. Elisabeth

doi:10.1016/j.neuroscience.2005.04.020

Cited by 43 publications

(33 citation statements)

References 82 publications

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“…In Cdk5-null mice, motor axons exhibit extensive anomalous branching patterns (37). Furthermore, inhibition of Cdk5 with roscovitine attenuates axon elongation (38). Thus, we propose that when Cdk5 is activated, CT␤2 is phosphorylated and activated, and consequently, neurite outgrowth and branching are promoted.…”

Section: Ct␤2 Is Abundant In Axons Andmentioning

confidence: 89%

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Phosphatidylcholine Biosynthesis via CTP:Phosphocholine Cytidylyltransferase β2 Facilitates Neurite Outgrowth and Branching

Carter

Demizieux

Campenot

et al. 2008

Journal of Biological Chemistry

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Hallmarks of neuronal differentiation are neurite sprouting, extension, and branching. We previously showed that increased expression of CTP:phosphocholine cytidylyltransferase ␤2 (CT␤2), an isoform of a key phosphatidylcholine (PC) biosynthetic enzyme, accompanies neurite outgrowth (Carter, J. M., Waite, K. A., Campenot, R. B., Vance, J. E., and Vance, D. E. (2003) J. Biol. Chem. 278, 44988 -44994). CT␤2 mRNA is highly expressed in the brain. We show that CT␤2 is abundant in axons of rat sympathetic neurons and retinal ganglion cells. We used RNA silencing to decrease CT␤2 expression in PC12 cells differentiated by nerve growth factor. In CT␤2-silenced cells, numbers of primary and secondary neurites were markedly reduced, suggesting that CT␤2 facilitates neurite outgrowth and branching. However, the length of individual neurites was significantly increased, and the total amount of neuronal membrane was unchanged. Neurite branching of PC12 cells is known to be inhibited by activation of Akt and promoted by the Akt inhibitor LY294002. Our experiments showed that LY294002 increases neurite sprouting and branching in control PC12 cells but not in CT␤2-deficient cells. CT␤2 was not phosphorylated in vitro by Akt. However, inhibition of Cdk5 by roscovitine blocked CT␤2 phosphorylation and reduced neurite outgrowth and branching. These results highlight the importance of CT␤2 in neurons for promoting neurite outgrowth and branching and represent the first identification of a lipid biosynthetic enzyme that facilitates these functions.

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Section: Ct␤2 Is Abundant In Axons Andmentioning

confidence: 89%

“…In addition, short term treatment of PC12 cells with roscovitine, a Cdk inhibitor, markedly decreased CT␤2 phosphorylation and neurite branching in intact cells. CT␤2 and Cdk5 (38) are both present within axons. Several lines of evidence suggest that Cdk5 promotes axon extension and impairs axon branching.…”

Section: Ct␤2 Is Abundant In Axons Andmentioning

confidence: 99%

Phosphatidylcholine Biosynthesis via CTP:Phosphocholine Cytidylyltransferase β2 Facilitates Neurite Outgrowth and Branching

Carter

Demizieux

Campenot

et al. 2008

Journal of Biological Chemistry

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“…These zig-zag stripes are valuable when analyzing cell behavior and signal-transduction events at substrate borders, where, for example, one part of a cell is adhering to a laminin substrate and the other part is contacting a substrate of different molecular nature 30 . Also, a novel technique allowing for microcontact printing of proteins on surfaces has been reported and offers a versatile tool to study the behavior of, for example, navigating growth cones in gradients of axon guidance cues 31 .…”

Section: Introductionmentioning

confidence: 99%

Stripe assay to examine axonal guidance and cell migration

et al. 2007

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Stripe assays have been widely employed as in vitro test systems to study the responses of growing axons, as well as migrating cells, to established or novel guidance molecules. We provide detailed protocols for both the original and the modified version of this assay, as they allow the analysis of the 'guidance properties' of active components present in crude membrane fractions or as purified molecules. Silicon matrices are used to produce striped patterns of active molecules on a surface (referred to as 'carpet'), followed by culturing of neurons, or any other cell type, on these carpets. After 1-2 days in culture, striped outgrowth of extending neuritesindicative of guided migration of cell processes-can be observed. We also discuss potential other applications (e.g., in neuronal regeneration and development) and modifications of the assay. The preparation of 10-12 carpets takes approximately 4-5 h. INTRODUCTIONThe stripe assay was originally designed by F. Bonhoeffer and co-workers 1,2 in the late 1980s to analyze fundamental axonal guidance mechanisms governing the formation of the topographic map established in the chick retino-tectal system (for review, see ref.3). Employing this assay, the presence of a graded distribution of repulsive axon guidance cues, present predominantly in posterior tectal membranes, was discovered. Subsequently, this assay was modified, permitting the identification of ephrin-As as the key components present in posterior membranes that are responsible for the repulsive properties 4-7 .The stripe assay has since been used to uncover guidance cues and mechanisms in many principal neuronal projections, including, for example, the hippocampal, thalamic and olfactory systems [8][9][10][11] . The stripe assay was also applied to investigate neurite outgrowth and guidance behavior related to neuronal regeneration 12-15 and branch formation 16 . Furthermore, the stripe assay has proven valuable in dissecting signaling cascades initiated downstream of axonal guidance receptors activated by ligands printed in a striped pattern [12][13][14][15] . In addition, the guidance properties of membrane-tethered molecules as well as the short-range action of secreted guidance molecules (such as Slits and Semaphorins) could be mimicked in vitro by this assay 17,18 . Also stripe assay experiments were conducted to unravel potential guidance properties of extracellular matrix components 19,20 and of cell adhesion molecules of the IgG superfamily 21 .Of note, the stripe assay was employed as an in vitro assay to investigate the navigation responses of both axonal growth cones toward guidance cues and of migrating cells 4,22,23 . With respect to the latter, neural crest cells 22 and oligodendrocytes 23,24 , but also non-neuronal cells such as tumor cells, have been studied 25 .The assay allows assessment of guidance activity of established molecules and also testing potential guidance properties of hitherto uncharacterized molecules such as RGM, the Wnt signaling inhibitor SFRP1 or the morphogen Sonic h...

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“…Cyclin-dependent kinase (Cdk) 5 activities within the axon play a significant role in the cytoskeletal dynamics of microtubules and actin neurofilaments (NFs), which determine axonal path and length. Specifically, cdk5 active complexes phosphorylate proteins that contribute to the stabilization or destabilization of microtubules, formation of neurofibrillary tangles, and axonal pathfinding (4)(5)(6).…”

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confidence: 99%

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

Tsai

Pokrass

Klauer

et al. 2015

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

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Dysregulation of cyclin-dependent kinase 5 (cdk5) per relative concentrations of its activators p35 and p25 is implicated in neurodegenerative diseases. P35 has a short t ½ and undergoes rapid proteasomal degradation in its membrane-bound myristoylated form. P35 is converted by calpain to p25, which, along with an extended t ½ , promotes aberrant activation of cdk5 and causes abnormal hyperphosphorylation of tau, thus leading to the formation of neurofibrillary tangles. The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperone that is implicated in neuronal survival. However, the specific role of the Sig-1R in neurodegeneration is unclear. Here we found that Sig-1Rs regulate proper tau phosphorylation and axon extension by promoting p35 turnover through the receptor's interaction with myristic acid. In Sig-1R-KO neurons, a greater accumulation of p35 is seen, which results from neither elevated transcription of p35 nor disrupted calpain activity, but rather to the slower degradation of p35. In contrast, Sig-1R overexpression causes a decrease of p35. Sig-1R-KO neurons exhibit shorter axons with lower densities. Myristic acid is found here to bind Sig-1R as an agonist that causes the dissociation of Sig-1R from its cognate partner binding immunoglobulin protein. Remarkably, treatment of Sig-1R-KO neurons with exogenous myristic acid mitigates p35 accumulation, diminishes tau phosphorylation, and restores axon elongation. Our results define the involvement of Sig-1Rs in neurodegeneration and provide a mechanistic explanation that Sig-1Rs help maintain proper tau phosphorylation by potentially carrying and providing myristic acid to p35 for enhanced p35 degradation to circumvent the formation of overreactive cdk5/p25.A xons are structurally and functionally distinct protrusions of neurons that modulate neurotransmitter release and neural function. Malfunction of axonal maintenance, regeneration, and target recognition contribute to CNS disorders such as Alzheimer's disease (AD), Parkinson's disease, stroke, and spinal cord injuries (1-3). Cyclin-dependent kinase (Cdk) 5 activities within the axon play a significant role in the cytoskeletal dynamics of microtubules and actin neurofilaments (NFs), which determine axonal path and length. Specifically, cdk5 active complexes phosphorylate proteins that contribute to the stabilization or destabilization of microtubules, formation of neurofibrillary tangles, and axonal pathfinding (4-6).Cdk5 is a ubiquitously expressed enzyme; however, its activator, p35, is almost exclusively expressed in neurons (7,8). Cdk5 signaling supports neurite projection and proper neuronal migration (9-11). Dysregulation of cdk5 activity leads to hyperphosphorylation of several substrates, including NF proteins and tau, which causes the formation of neurofibrillary tangles (6, 12). Although the kinetics of cdk5 activity when in complex with p35 or p25 are the same, cdk5/p25 complexes are proposed to be responsible for neurodegenerative pathophysiology because of their longer duration o...

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Role of cyclin-dependent kinase 5 and its activator P35 in local axon and growth cone stabilization

Cited by 43 publications

References 82 publications

Phosphatidylcholine Biosynthesis via CTP:Phosphocholine Cytidylyltransferase β2 Facilitates Neurite Outgrowth and Branching

Phosphatidylcholine Biosynthesis via CTP:Phosphocholine Cytidylyltransferase β2 Facilitates Neurite Outgrowth and Branching

Stripe assay to examine axonal guidance and cell migration

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

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