p35 and p39 Are Essential for Cyclin-Dependent Kinase 5 Function during Neurodevelopment

Ko, Jane P.; Humbert, Sandrine; Bronson, Roderick T.; Takahashi, Satoru; Kulkarni, Ashok B.; Li, En; Tsai, Li‐Huei

doi:10.1523/jneurosci.21-17-06758.2001

Cited by 359 publications

(332 citation statements)

References 62 publications

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“…We had earlier gen- erated Cdk5Ϫ͞Ϫ mice that displayed a striking CNS phenotype associated with mortality during the late embryonic stage and at birth (5). Additionally, we and others have also generated p35Ϫ͞Ϫ and p39Ϫ͞Ϫ mice that provided insights into the molecular roles of these Cdk5 activators (22)(23)(24). However, none of these mouse models provided the benefit of conditional deletion of Cdk5 gene in whole or specific areas of the adult CNS.…”

Section: Discussionmentioning

confidence: 99%

Perinatal abrogation of Cdk5 expression in brain results in neuronal migration defects

Hirasawa

Ohshima

Takahashi

et al. 2004

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

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Cyclin-dependent kinase 5 (Cdk5) is essential for the proper development of the CNS, as is evident from the perinatal lethality of conventional Cdk5 knockout (Cdk5؊͞؊) mice. Cdk5 is also implicated in numerous complex functions of the adult CNS such as synaptic transmission, synaptic plasticity, and neuronal signaling. To elucidate the molecular roles of Cdk5 in the adult CNS, we have abrogated neuronal expression of Cdk5 in perinatal mice by using a cre-loxP system. The Cdk5-loxP flanked mice were crossed with the cre-transgenic mice in which the cre expression is driven by the murine neurofilament-heavy chain promoter, resulting in generation of viable Cdk5 conditional knockout mice with the restricted deletion of the Cdk5 gene in specific neurons beginning around embryonic day 16.5. Twenty-five percent of the Cdk5 conditional knockout mice carrying the heterozygous cre allele had neuronal migration defects confined to brain areas where neuronal migration continues through the perinatal period. These results indicate that abrogation of Cdk5 expression in mature neurons results in a viable mouse model that offers further opportunities to investigate the molecular roles of Cdk5 in the adult CNS.C yclin-dependent kinase 5 (Cdk5) is a small serine͞threonine kinase belonging to the cdk family of proline-directed kinases. Unlike other cdks, Cdk5 activity is detected mainly in postmitotic neurons (1). Association of Cdk5 with its neuronspecific regulatory subunit, either p35 or its isoform p39, is critical for its kinase activity (2-4). We have earlier reported in vivo roles of Cdk5 with conventional Cdk5Ϫ͞Ϫ mice (5, 6). These mice exhibit embryonic lethality and disruption of cortical laminar structures due to defective neuronal migration (5, 6). Chromatolytic changes such as a ballooned cell soma with eccentric nuclei were also observed in the neurons of the Cdk5Ϫ͞Ϫ mice (5). Perikaryal accumulation of phosphorylated murine neurofilament-heavy chain (pNFH) was seen in the cell soma of the motor neurons in the brainstem and spinal cord (5). Because of the embryonic lethality of Cdk5Ϫ͞Ϫ mice, it was not possible to carry out further analysis of this neuronal pathology in the adult CNS.Cdk5 is believed to phosphorylate numerous substrates in neurons and thereby regulate many cellular processes of the mature CNS such as phosphorylation of neuronal cytoskeletons (7-10), synaptic transmission (11, 12), and dopaminergic signaling (13). To determine the role of Cdk5 in the adult CNS, we generated a conditional knockout (KO) mouse by using a cre-loxP system in which the Cdk5 gene was disrupted in the CNS in a temporally and spatially regulated manner. To abrogate Cdk5 expression, we generated transgenic mice in which the Cdk5 gene was flanked by loxP motifs, and then crossed them with the previously described heterozygous murine (m) NFHcre mouse line 12, in which the cre recombinase is expressed only in certain neurons beginning around embryonic day 16.5 (E16.5) (14). Unlike Cdk5Ϫ͞Ϫ mice, the Cdk5 conditional KO mice are vi...

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Section: Discussionmentioning

confidence: 99%

Perinatal abrogation of Cdk5 expression in brain results in neuronal migration defects

Hirasawa

Ohshima

Takahashi

et al. 2004

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

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“…Cdk5Ϫ/Ϫ Mouse Brain-Previous studies have shown that neuronal Cdk5 activity is necessary for survival and nervous system development (29,30,46). Phospholipid kinases, the phosphoinositide kinases, are responsible for the phospholipid phosphorylation.…”

Section: Reduced Brain Lipid Phosphorylation and Pi3k Activity Inmentioning

confidence: 99%

Cyclin-dependent Kinase-5 Is Involved in Neuregulin-dependent Activation of Phosphatidylinositol 3-Kinase and Akt Activity Mediating Neuronal Survival

Jaffe

et al. 2003

Journal of Biological Chemistry

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The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway plays an important role in mediating survival signals in wide variety of neurons and cells. Recent studies show that Akt also regulates metabolic pathways to regulate cell survival. In this study, we reported that cyclin-dependent kinase-5 (Cdk5) regulates Akt activity and cell survival through the neuregulin-mediated PI 3-kinase signaling pathway. We found that brain extracts of Cdk5؊/؊ mice display a lower PI 3-kinase activity and phosphorylation of Akt compared with that in wild type mice. Moreover, we demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival. These findings suggest that Cdk5 may exert a key role in promoting neuronal survival by regulating Akt activity through the neuregulin/PI 3-kinase signaling pathway.Cyclin-dependent kinase 5 (Cdk5) 1 is a serine/threonine kinase, which is predominantly expressed in postmitotic neurons (1). Cdk5 kinase activity requires association with its neuronspecific activators, p35 and p39. Cdk5 kinase activity is essential for neuronal migration, neurite outgrowth, and laminar configuration of the cerebral cortex (2-4). Recently, Cdk5 has been suggested as contributing to the control of neuronal positioning in Reelin signaling during neural development (5) and to mediate neuronal guidance by regulating semaphorin-3A with Fyn kinase (6). Cdk5 and p35 have recently also been shown to regulate presynaptic and postsynaptic activity by phosphorylating Munc-18, amphiphysin, and the NR2A subunit of the N-methyl-D-aspartate receptor (7-11). Cdk5 activity also regulates dopamine signaling by phosphorylating DARPP-32 protein (12) and has been shown to up-regulate the expression of acetylcholine receptor at the neuromuscular junction (13). These studies indicate that Cdk5 is a multifunctional protein kinase in the central nervous system. Cdk5 has been implicated in both cell survival and programmed cell death in neuronal and nonneuronal systems (14,15). Cells induced to apoptosis by exogenous signals such as staurosporin display increased Cdk5 activity (16,17). Recently, Cdk5 in association with p25, a truncated form of p35, has been thought to be deregulated to produce hyperphosphorylated tau protein and to disrupt the neuronal cytoskeleton, and it may be involved in neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral secrosis, Parkinson's disease, and Niemann-Pick disease (18 -23). On the other hand, Cdk5 may also be involved in neuronal survival. Cdk5 knockout mice exhibit a unique phenotype with perinatal mortality, associated with extensively disrupted cerebral cortical layering due to abnormal neuronal migration, absence of cerebella foliation, and degeneration of neurons...

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“…Several neuronal and nonneuronal substrates are phosphorylated by Cdk5 (19), and the list of substrates is increasing (20). Earlier studies showed that Cdk5 knockout and p35/p39 doubleknockout mice are embryonically lethal with neuronal migration defects (21,22), whereas p35-knockout mice show inverted neuronal layering (23) with a concurrent attenuated response to noxious heat; conversely, mice overexpressing p35 were hyperalgesic (15).…”

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confidence: 99%

Cyclin-dependent kinase 5 modulates nociceptive signaling through direct phosphorylation of transient receptor potential vanilloid 1

Pareek¹,

Keller

Kesavapany³

et al. 2007

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

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108

128

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Transient receptor potential vanilloid 1 (TRPV1), a ligand-gated cation channel highly expressed in small-diameter sensory neurons, is activated by heat, protons, and capsaicin. The phosphorylation of TRPV1 provides a versatile regulation of intracellular calcium levels and is critical for TRPV1 function in responding to a pain stimulus. We have previously reported that cyclin-dependent kinase 5 (Cdk5) activity regulates nociceptive signaling. In this article we report that the Cdk5-mediated phosphorylation of TRPV1 at threonine-407 can modulate agonist-induced calcium influx. Inhibition of Cdk5 activity in cultured dorsal root ganglia neurons resulted in a significant reduction of TRPV1-mediated calcium influx, and this effect could be reversed by restoring Cdk5 activity. Primary nociceptor-specific Cdk5 conditional-knockout mice showed reduced TRPV1 phosphorylation, resulting in significant hypoalgesia. Thus, the present study indicates that Cdk5-mediated TRPV1 phosphorylation is important in the regulation of pain signaling.p35 ͉ pain I n general nociceptive (painful) neural signals originate from sensory neurons in peripheral tissues and are transmitted to second-order neurons in the spinal cord, which then convey the message to specific nuclei in the brain for perception of pain. Nociception results from the activation of molecular and cellular mechanisms in damaged tissue, sensory neurons, and the spinal cord. Many cellular pathways have been implicated in nociceptive signaling, but their precise molecular mechanisms have not been clearly defined. Abnormalities in molecular pathways underlying nociceptive processes may result in chronic pain conditions. It follows that a detailed characterization of these pathways is necessary for developing effective strategies to treat pain. Signal transduction mechanisms activated by nociceptive stimuli have not been fully characterized. Recent advances, especially the cloning and characterization of the capsaicin receptor (also known as vanilloid receptor 1), remarkably improved our understanding of signal transduction in nociceptive neurons. Transient receptor potential vanilloid 1 (TRPV1) is a member of the transient receptor potential family (1, 2). It is a polymodal ligand-gated ion channel that is expressed in smalldiameter sensory neurons (C-fibers) and is activated by heat, protons, anandamide, and leukotrienes (3-7). TRPV1-knockout mice show reduced thermal hyperalgesia after inflammation (8, 9) and reduced nociceptive responsiveness in a model of bone cancer pain (10). TRPV1 has been connected to a broad spectrum of physiological conditions and diseases such as thermal hyperalgesia, allodynia, inf lammatory bowel disease, Crohn's disease, vulvodynia, osteoarthritis, pancreatitis, gastroesophageal reflux disease, bladder disease, cystitis, and asthma (11). There is mounting evidence that TRPV1 is subject to multiple interacting levels of control. Phosphorylation of TRPV1 is critical for its function in response to nociceptive stimuli (12)(13)(14). We demonstrat...

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p35 and p39 Are Essential for Cyclin-Dependent Kinase 5 Function during Neurodevelopment

Cited by 359 publications

References 62 publications

Perinatal abrogation of Cdk5 expression in brain results in neuronal migration defects

Perinatal abrogation of Cdk5 expression in brain results in neuronal migration defects

Cyclin-dependent Kinase-5 Is Involved in Neuregulin-dependent Activation of Phosphatidylinositol 3-Kinase and Akt Activity Mediating Neuronal Survival

Cyclin-dependent kinase 5 modulates nociceptive signaling through direct phosphorylation of transient receptor potential vanilloid 1

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