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Li-huei Tsai - One of the best experts on this subject based on the ideXlab platform.
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Cyclin Dependent Kinase 5 (Cdk5) - Cyclin Dependent Kinase 5 (Cdk5)
2020Co-Authors: Nancy Y. Ip, Li-huei TsaiAbstract:Neuronsmigrate from proliferative zone to their final position during brain development. Cyclin-Dependent Kinase 5 (Cdk5) plays an important role in neuronal migration to establish a proper structure of the brain. Analyses of Cdk5/p35-deficient mice have provided the knowledge about the role of Cdk5/p35 in neuronal migration. Over the past years, migration-related substrates of Cdk5 have been identified. Imaging analyses of neuronal migration of Cdk5/p35-deficient neurons have begun to elucidate how proper phosphorylations of these proteins by Cdk5/p35 are required for the regulation of cytoskeletal dynamics and cellular adhesion during neuronal migration. Expression of Cdk5, p35, and p39 During Brain Development Cyclin-Dependent Kinase 5 (Cdk5), a proline-directed serine (Ser)/threonine (Thr) Kinase, had been identified as a member of the CDK family because of its close sequence homology to human CDC2 (Meyerson et al., 1992; Hellmich et al., 1992; Lew et al., 1992). Since the activity of Cdk5 is regulated by binding it with one of its neuron-specific regulatory subunits, either p35 (Lew et al., 1994; Tsai et al., 1994) or its isoform p39 (Tang et al., 1995), its activity is correlated with the level of expression of p35 and p39. Cdk5 expression is basically ubiquitous, and it is abundant in neuronal cells (Tsai et al., 1993). Expression of p35 and p39 overlaps throughout the central nervous system (CNS) during brain development, except for their expression in the cerebral cortex in the early stage, where only p35 is expressed till around E16 (Ohshima et al., 2001). High Cdk5 activity during neuronal differentiation and brain development reflects high-level expression of p35 and p39 (Tsai et al., 1993). T. Ohshima Laboratory for Molecular Brain Science, Department of Life Science and Medical Bio-Science, Science and Engineering, Waseda University, Tokyo 169-8555, Japan e-mail: ohshima@waseda.jp N.Y. Ip, L.-H. Tsai (eds.), Cyclin Dependent Kinase 5 (Cdk5), DOI: 10.1007/978-0-387-78887-6_1, Springer ScienceþBusiness Media, LLC 2008 1 Cdk5/p35 Deficiency Causes Neuronal Migration Defects in CNS Studies of the phenotypes of knockout (KO)mice have shown that Cdk5 and p35 are critical for migration of neurons to their final positions in the developing brain (Ohshima and Mikoshiba, 2002; Dhavan and Tsai, 2002). Migration defects in the cortical neurons of Cdk5 KO mice result in disruption of the laminar structures in the cerebral cortex, olfactory bulb, hippocampus, and cerebellum (Ohshima et al., 1996). p35 KO mice display a milder phenotype than Cdk5 KO mice because of the redundancy of p39 (Chae et al., 1997; Ohshima et al., 2001). p39 KO mice display no phenotype; however, p35 and p39 double KOmice display a phenotype identical to that of Cdk5 KOmice (Ko et al., 2001), confirming the redundancy of these subunits. Neuronal migration defects in Cdk5 KOmice are observed in many types of neuronal migration, but not in all types. These observations about Cdk5/p35 mutant mice indicate the occurrence of Cdk5-dependent and -independent neuronal migration. For example, radial migration of cortical neurons is Cdk5 dependent, but migration of subplate neurons seems to be Cdk5 independent in the cerebral cortex (Gilmore andHerrup, 2001). Tangentialmigration ofGABAergic neurons from ganglionic eminence to cerebral cortex is also Cdk5 independent (Gilmore and Herrup, 2001). Migration along radial glial fibers is Cdk5 dependent in many cases including radial migration of cerebral cortical neurons and inward migration of granule cells in the cerebellum (Table 1). The list of examples of Cdk5-depedent migration (Table 1) will be expanded by further analysis of mutant mice. Table 1 Comparison of migration defects in neuronal types in CNS among mutant mice Structure or neuronal type in CNS Cdk5 KO p35 KO Reeler/Dab1 mutant Olfactory bulb mitral cell þþ – –
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Comprar Cyclin Dependent Kinase 5 (Cdk5) | Ip, Nancy Y. | 9780387788869 | Springer
2020Co-Authors: Nancy Y. Ip, Li-huei TsaiAbstract:Tienda online donde Comprar Cyclin Dependent Kinase 5 (Cdk5) al precio 122,84 € de Ip, Nancy Y. | Tsai, Li-Huei, tienda de Libros de Medicina, Libros de Biologia - Biologia molecular y celular
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Cyclin-Dependent Kinase 5 permits efficient cytoskeletal remodeling--a hypothesis on neuronal migration.
Cerebral cortex (New York N.Y. : 1991), 2020Co-Authors: Benjamin Adam Samuels, Li-huei TsaiAbstract:Migration of neurons to their proper position underlies mammalian brain development. To remain on the proper path, a migrating neuron needs to detect various external signals and respond by efficiently remodeling its cytoskeleton. Cyclin-Dependent Kinase 5 (Cdk5), a member of the Cyclin-Dependent Kinase family, regulates neuronal migration by phosphorylating a number of intracellular substrates. Deficiencies in Cdk5 preferentially cause impairments in radial glia-guided migration, a process that involves complex remodeling of the cytoskeleton, particularly the microtubules. Furthermore, the defined substrates of Cdk5 that are important for migration generally link Cdk5 to the cytoskeleton. Interestingly, none of these phosphorylation events seem to directly control the activity of the substrates. Taken together, these findings support a model in which Cdk5 does not directly control the detection of any specific external signals but instead regulates efficient remodeling of the cytoskeleton through phosphorylation of multiple substrates.
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Cyclin-Dependent Kinase 5 (Cdk5): Linking Synaptic Plasticity and Neurodegeneration
Cyclin Dependent Kinase 5 (Cdk5), 2008Co-Authors: Andre Fischer, Li-huei TsaiAbstract:It is well established that Cyclin-Dependent Kinase 5 (Cdk5) is critically involved in neurodevelopmental processes. In addition, recent data point toward an important role of Cdk5 in regulating synaptic plasticity, learning, and memory in the adult brain. However, aberrant Cdk5 activity has been implicated in various neurodegenerative diseases such as Alzheimer’s disease. Deregulation of Cdk5 has been attributed to calpain-mediated cleavage of the Cdk5 activator p35 to the N-terminally truncated p25 protein. p25 levels are elevated in many neurodegenerative diseases and implicated in neuronal cell death in vitro and in vivo. More importantly, p25/Cdk5 causes hyperphosphorylation of tau and affects processing of APP, leading to increased levels of toxic Aβ-peptides. Surprisingly, recent data indicate that in vivo p25 is not toxic per se but that a transient increase in p25 levels may even facilitate neuroplasticity. Here we will review these recent developments and propose a scenario in which p25 generation during aging and Alzheimer’s disease might initially be a compensatory phenomenon to enhance neuroplasticity but eventually contributes to the pathogenesis of Alzheimer’s disease when chronically elevated.
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Cyclin-Dependent Kinase 5 Permits Efficient Cytoskeletal Remodeling—a Hypothesis on Neuronal Migration
Cerebral Cortex, 2006Co-Authors: Benjamin Adam Samuels, Li-huei TsaiAbstract:Migration of neurons to their proper position underlies mammalian brain development. To remain on the proper path, a migrating neuron needs to detect various external signals and respond by efficiently remodeling its cytoskeleton. Cyclin-Dependent Kinase 5 (Cdk5), a member of the Cyclin-Dependent Kinase family, regulates neuronal migration by phosphorylating a number of intracellular substrates. Deficiencies in Cdk5 preferentially cause impairments in radial glia--guided migration, a process that involves complex remodeling of the cytoskeleton, particularly the microtubules. Furthermore, the defined substrates of Cdk5 that are important for migration generally link Cdk5 to the cytoskeleton. Interestingly, none of these phosphorylation events seem to directly control the activity of the substrates. Taken together, these findings support a model in which Cdk5 does not directly control the detection of any specific external signals but instead regulates efficient remodeling of the cytoskeleton through phosphorylation of multiple substrates.
Harish C. Pant - One of the best experts on this subject based on the ideXlab platform.
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Activation of Cyclin-Dependent Kinase 5 mediates orofacial mechanical hyperalgesia
Molecular Pain, 2013Co-Authors: Michaela Prochazkova, Harish C. Pant, Anita Terse, Niranjana D. Amin, Bradford Hall, Elias Utreras, Ashok B. KulkarniAbstract:Background Cyclin-Dependent Kinase 5 (Cdk5) is a unique member of the serine/threonine Kinase family. This Kinase plays an important role in neuronal development, and deregulation of its activity leads to neurodegenerative disorders. Cdk5 also serves an important function in the regulation of nociceptive signaling. Our previous studies revealed that the expression of Cdk5 and its activator, p35, is upregulated in nociceptive neurons during peripheral inflammation. The aim of the present study was to characterize the involvement of Cdk5 in orofacial pain. Since mechanical hyperalgesia is the distinctive sign of many orofacial pain conditions, we adapted an existing orofacial stimulation test to assess the behavioral responses to mechanical stimulation in the trigeminal region of the transgenic mice with either reduced or increased Cdk5 activity.
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Specific inhibition of Cyclin-Dependent Kinase 5 activity induces motor neuron development in vivo.
Biochemical and Biophysical Research Communications, 2009Co-Authors: Jyotshnabala Kanungo, Niranjana D. Amin, Ya-li Zheng, Ramani Ramchandran, Sukhbir Kaur, Harish C. PantAbstract:Cyclin-Dependent Kinase 5 (cdk5) is a ubiquitous protein activated by specific activators, p35 and p39. Cdk5 regulates neuronal migration, differentiation, axonogenesis, synaptic transmission and apoptosis. However, its role in motor neuron development remains unexplored. Here, using gain and loss-of-function analyses in developing zebrafish embryos, we report that cdk5 plays a critical role in spinal and cranial motor neuron development. Cdk5 knockdown results in supernumerary spinal and cranial motor neurons. While a dominant negative, Kinase-dead cdk5 promotes the generation of supernumerary motor neurons; over-expression of cdk5 suppresses motor neuron development. Thus, modulating cdk5 activity seems promising in inducing motor neuron development in vivo.
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Cloning and characterization of zebrafish (Danio rerio) Cyclin- dependent Kinase 5
Neuroscience Letters, 2006Co-Authors: Jyotshnabala Kanungo, Bing-sheng Li, Moloy Goswami, Ya-li Zheng, Ramani Ramchandran, Harish C. PantAbstract:Cyclin-Dependent Kinase 5 (cdk5) is a ubiquitous protein activated by neuron-specific activators, p35 and p39. Cdk5 regulates neuronal migration, differentiation, axonogenesis, synaptic transmission and apoptosis. However, its role in primary neurogenesis remains unexplored. Here, we have cloned and characterized the zebrafish cdk5 ortholog. Zebrafish cdk5 is 96% identical to its human counterpart. In situ hybridization analyses demonstrated that zebrafish cdk5 transcripts are ubiquitously expressed as early as the blastula stage. At 11.5 h of development, cdk5 transcripts were present in the neural plate at the domains where primary neurons begin to be specified. RT-PCR analyses showed equal levels of cdk5 transcripts up to 72 h of development. SiRNA-mediated cdk5 knockdown resulted in a reduction in primary sensory neurons of the trigeminal ganglia of the peripheral nervous system, suggesting that cdk5 plays a crucial role in the development of the peripheral nervous system.
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Cyclin-Dependent Kinase 5 influences Rohon-Beard neuron survival in zebrafish.
Journal of Neurochemistry, 2006Co-Authors: Jyotshnabala Kanungo, Bing-sheng Li, Ya-li Zheng, Harish C. PantAbstract:Cyclin-Dependent Kinase 5 (cdk5), a member of the Cyclin-Dependent Kinase family, is expressed predominantly in post-mitotic cell populations. Unlike the other cdks, cdk5 is abundant and most active in differentiated neurons. Here, we describe the function of a cdk5 ortholog in zebrafish. Cdk5 catalytic activity is meager but present in early stages of development. However, at 24 h post-fertilization (hpf), the activity is remarkably higher and continues to be high through 48 and 72 hpf. Knocking down cdk5 by micro-injection of a specific siRNA resulted in decreased cdk5 protein level accompanied by reduced Kinase activity. In the cdk5 siRNA-injected embryos, the number of primary sensory Rohon-Beard (RB) neurons was significantly reduced and there were more apoptotic cells in the brain. These phenotypes were rescued by co-injection of cdk5 mRNA. Within the first two days of development, RB neurons undergo apoptosis in zebrafish. To examine whether cdk5 has a role in RB neuron survival, cdk5 mRNA was injected into the one- to two-cell embryos. In these embryos, RB neuron apoptosis was inhibited compared with the uninjected control embryos. These results suggest that in zebrafish, cdk5 influences RB neuron survival and potentially regulates early neuronal development.
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Cyclin-Dependent Kinase 5 activity regulates pain signaling
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Tej K. Pareek, Roscoe O. Brady, Harish C. Pant, Jason M. Keller, Sashi Kesavapany, Michael J. Iadarola, Ashok B. KulkarniAbstract:Several molecules and cellular pathways have been implicated in nociceptive signaling, but their precise molecular mechanisms have not been clearly defined. Cyclin-Dependent Kinase 5 (Cdk5) is a proline-directed serine/threonine Kinase implicated in the development and disease of the mammalian nervous system. The precise role of this Kinase in sensory pathways has not been well characterized. Here we report a molecular role for Cdk5 in nociception. We identified the expression of Cdk5 and its activator p35 in nociceptive neurons, which is modulated during a peripheral inflammatory response. Increased calpain activity in sensory neurons after inflammation resulted in the cleavage of p35 to p25, which forms a more stable complex with Cdk5 and, consequently, leads to elevation of Cdk5 activity. p35 knockout mice (p35–/–), which exhibit significantly decreased Cdk5 activity, showed delayed responses to painful thermal stimulation compared with WT controls. In contrast, mice overexpressing p35, which exhibit elevated levels of Cdk5 activity, were more sensitive to painful thermal stimuli than were controls. In conclusion, our data demonstrate a role for Cdk5/p35 activity in primary afferent nociceptive signaling, suggesting that Cdk5/p35 may be a target for the development of analgesic drugs.
Ashok B. Kulkarni - One of the best experts on this subject based on the ideXlab platform.
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Cyclin-Dependent Kinase 5 modulates the P2X2a receptor channel gating through phosphorylation of C-terminal threonine 372.
Pain, 2017Co-Authors: Claudio Coddou, Anita Terse, Bradford Hall, Rodrigo Sandoval, Patricio A. Castro, Pablo Lazcano, María José Hevia, Milos B. Rokic, Christian Gonzalez-billault, Ashok B. KulkarniAbstract:AbstractThe purinergic P2X2 receptor (P2X2R) is an adenosine triphosphate–gated ion channel widely expressed in the nervous system. Here, we identified a putative Cyclin-Dependent Kinase 5 (Cdk5) phosphorylation site in the full-size variant P2X2aR (372TPKH375), which is absent in the splice variant
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Regulation of Sox6 by cyclin dependent Kinase 5 in brain.
PLOS ONE, 2014Co-Authors: Parvathi Rudrabhatla, Elias Utreras, Howard Jaffe, Ashok B. KulkarniAbstract:Cyclin dependent Kinase 5 (Cdk5) is a proline-directed Ser/Thr Kinase involved in various biological functions during normal brain development and neurodegeneration. In brain, Cdk5 activity is specific to post-mitotic neurons, due to neuronal specific expression of its activator p35. The biological functions of Cdk5 have been ascribed to its cytoplasmic substrates, however not much is known in nucleus. Here, we show that nuclear transcription factor Sox6 is a direct nuclear target of Cdk5. Sox6 is expressed in Tuj1 positive neurons, suggesting that Sox6 is expressed in differentiating neurons. The expression of Sox6 is high in mitotic nuclei during embryonic day 12 (E12) and gradually decreases during development into adult. On the other hand, Cdk5 expression gradually increases during its development. We show that Sox6 is expressed in mitotic nuclei in embryonic day 12 (E12) and in migrating neurons of E16. Sox6 is phosphorylated in vivo. Sox6 was detected by phospho-Ser/Thr and phospho-Ser/Thr-Pro and MPM-2 (Mitotic protein #2) antibodies in brain. Furthermore, calf intestinal alkaline phosphatase (CIAP) digestion resulted in faster migration of Sox6 band. The GST-Sox6 was phosphorylated by Cdk5/p35. The mass spectrometry analysis revealed that Sox6 is phosphorylated at T119PER motif. We show that Sox6 steady state levels are regulated by Cdk5. Cdk5 knockout mice die in utero and Sox6 protein expression is remarkably high in Cdk5−/− brain, however, there is no change in mRNA expression, suggesting a post-translational regulation of Sox6 by Cdk5. Transfection of primary cortical neurons with WT Cdk5 reduced Sox6 levels, while dominant negative (DN) Cdk5 and p35 increased Sox6 levels. Thus, our results indicate that Cdk5 regulates Sox6 steady state protein level that has an important role in brain development and function.
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Activation of Cyclin-Dependent Kinase 5 mediates orofacial mechanical hyperalgesia
Molecular Pain, 2013Co-Authors: Michaela Prochazkova, Harish C. Pant, Anita Terse, Niranjana D. Amin, Bradford Hall, Elias Utreras, Ashok B. KulkarniAbstract:Background Cyclin-Dependent Kinase 5 (Cdk5) is a unique member of the serine/threonine Kinase family. This Kinase plays an important role in neuronal development, and deregulation of its activity leads to neurodegenerative disorders. Cdk5 also serves an important function in the regulation of nociceptive signaling. Our previous studies revealed that the expression of Cdk5 and its activator, p35, is upregulated in nociceptive neurons during peripheral inflammation. The aim of the present study was to characterize the involvement of Cdk5 in orofacial pain. Since mechanical hyperalgesia is the distinctive sign of many orofacial pain conditions, we adapted an existing orofacial stimulation test to assess the behavioral responses to mechanical stimulation in the trigeminal region of the transgenic mice with either reduced or increased Cdk5 activity.
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Cyclin-Dependent Kinase 5 is required for normal cerebellar development.
Molecular and Cellular Neuroscience, 2012Co-Authors: A. Kumazawa, Ashok B. Kulkarni, Naoki Mita, Motoyuki Hirasawa, T. Adachi, Hiromi Suzuki, N. Shafeghat, Katsuhiko Mikoshiba, Takafumi Inoue, Toshio OhshimaAbstract:Abstract Cyclin-Dependent Kinase 5 (Cdk5) is a serine/threonine Kinase, and its Kinase activity is dependent upon its association with either of the activating subunits p35 or p39, which are mainly expressed in neurons. We previously reported that Cdk5 knockout (KO) mice exhibit perinatal lethality, defective neuronal migration, and abnormal positioning of neurons in the facial motor nucleus and inferior olive in the hindbrain and Purkinje cells (PCs) in the cerebellum. In this study, we focused on the analysis of the role of Cdk5 in cerebellar development. For this purpose we generated midbrain–hindbrain-specific Cdk5 conditional knockout (MHB-Cdk5 KO) mice because the cerebellum develops postnatally, whereas Cdk5 KO mice die perinatally. Histological analysis of the MHB-Cdk5 KO mice revealed a significant size reduction of the cerebellum. In addition, profound disturbance of inward migration of granule cells (GC) was observed in the developing cerebellum. A normal dendritic development of the Purkinje cells (PCs) was disturbed in MHB-Cdk5 KO mice. Cultured Cdk5-null PCs showed similar dendritic abnormalities. These results indicate that Cdk5/p35 plays an important role in neuronal migration of PCs and GCs and dendrite formation of PCs in cerebellar development.
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Conditional deletion of Cyclin-Dependent Kinase 5 in primary sensory neurons leads to atypical skin lesions.
Cell Cycle, 2008Co-Authors: Brenda Saikkonen, Tej K. Pareek, Nitin Agarwal, Alfredo A. Molinolo, Martin Kriete, Ashok B. KulkarniAbstract:The key role of Cyclin-Dependent Kinase 5 (Cdk5) in neuronal function has been well established but understanding of its importance in sensory pathways is in its infancy. Recently we described the important role of Cdk5 in pain signaling. Our studies indicated that conditional deletion of Cdk5 in small sensory neurons causes hypoalgesia. In current study, we identified development of atypical non-healing skin lesions in these mutant mice during the general colony maintenance. Detailed examination of these lesions clearly distinguishes them from ulcerative dermatitis. Here we hypothesize that these skin lesions are due to general sensation loss in these mice as evident from deep skin scratches that turn into unhealed wounds.
Nancy Y. Ip - One of the best experts on this subject based on the ideXlab platform.
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Cyclin Dependent Kinase 5 (Cdk5) - Cyclin Dependent Kinase 5 (Cdk5)
2020Co-Authors: Nancy Y. Ip, Li-huei TsaiAbstract:Neuronsmigrate from proliferative zone to their final position during brain development. Cyclin-Dependent Kinase 5 (Cdk5) plays an important role in neuronal migration to establish a proper structure of the brain. Analyses of Cdk5/p35-deficient mice have provided the knowledge about the role of Cdk5/p35 in neuronal migration. Over the past years, migration-related substrates of Cdk5 have been identified. Imaging analyses of neuronal migration of Cdk5/p35-deficient neurons have begun to elucidate how proper phosphorylations of these proteins by Cdk5/p35 are required for the regulation of cytoskeletal dynamics and cellular adhesion during neuronal migration. Expression of Cdk5, p35, and p39 During Brain Development Cyclin-Dependent Kinase 5 (Cdk5), a proline-directed serine (Ser)/threonine (Thr) Kinase, had been identified as a member of the CDK family because of its close sequence homology to human CDC2 (Meyerson et al., 1992; Hellmich et al., 1992; Lew et al., 1992). Since the activity of Cdk5 is regulated by binding it with one of its neuron-specific regulatory subunits, either p35 (Lew et al., 1994; Tsai et al., 1994) or its isoform p39 (Tang et al., 1995), its activity is correlated with the level of expression of p35 and p39. Cdk5 expression is basically ubiquitous, and it is abundant in neuronal cells (Tsai et al., 1993). Expression of p35 and p39 overlaps throughout the central nervous system (CNS) during brain development, except for their expression in the cerebral cortex in the early stage, where only p35 is expressed till around E16 (Ohshima et al., 2001). High Cdk5 activity during neuronal differentiation and brain development reflects high-level expression of p35 and p39 (Tsai et al., 1993). T. Ohshima Laboratory for Molecular Brain Science, Department of Life Science and Medical Bio-Science, Science and Engineering, Waseda University, Tokyo 169-8555, Japan e-mail: ohshima@waseda.jp N.Y. Ip, L.-H. Tsai (eds.), Cyclin Dependent Kinase 5 (Cdk5), DOI: 10.1007/978-0-387-78887-6_1, Springer ScienceþBusiness Media, LLC 2008 1 Cdk5/p35 Deficiency Causes Neuronal Migration Defects in CNS Studies of the phenotypes of knockout (KO)mice have shown that Cdk5 and p35 are critical for migration of neurons to their final positions in the developing brain (Ohshima and Mikoshiba, 2002; Dhavan and Tsai, 2002). Migration defects in the cortical neurons of Cdk5 KO mice result in disruption of the laminar structures in the cerebral cortex, olfactory bulb, hippocampus, and cerebellum (Ohshima et al., 1996). p35 KO mice display a milder phenotype than Cdk5 KO mice because of the redundancy of p39 (Chae et al., 1997; Ohshima et al., 2001). p39 KO mice display no phenotype; however, p35 and p39 double KOmice display a phenotype identical to that of Cdk5 KOmice (Ko et al., 2001), confirming the redundancy of these subunits. Neuronal migration defects in Cdk5 KOmice are observed in many types of neuronal migration, but not in all types. These observations about Cdk5/p35 mutant mice indicate the occurrence of Cdk5-dependent and -independent neuronal migration. For example, radial migration of cortical neurons is Cdk5 dependent, but migration of subplate neurons seems to be Cdk5 independent in the cerebral cortex (Gilmore andHerrup, 2001). Tangentialmigration ofGABAergic neurons from ganglionic eminence to cerebral cortex is also Cdk5 independent (Gilmore and Herrup, 2001). Migration along radial glial fibers is Cdk5 dependent in many cases including radial migration of cerebral cortical neurons and inward migration of granule cells in the cerebellum (Table 1). The list of examples of Cdk5-depedent migration (Table 1) will be expanded by further analysis of mutant mice. Table 1 Comparison of migration defects in neuronal types in CNS among mutant mice Structure or neuronal type in CNS Cdk5 KO p35 KO Reeler/Dab1 mutant Olfactory bulb mitral cell þþ – –
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Comprar Cyclin Dependent Kinase 5 (Cdk5) | Ip, Nancy Y. | 9780387788869 | Springer
2020Co-Authors: Nancy Y. Ip, Li-huei TsaiAbstract:Tienda online donde Comprar Cyclin Dependent Kinase 5 (Cdk5) al precio 122,84 € de Ip, Nancy Y. | Tsai, Li-Huei, tienda de Libros de Medicina, Libros de Biologia - Biologia molecular y celular
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Cyclin-Dependent Kinase 5 in Axon Growth and Regeneration
International Review of Neurobiology, 2020Co-Authors: Tao Ye, Amy K.y. Fu, Nancy Y. IpAbstract:Abstract Injury to the central nervous system often leads to irreversible deficits because of the failure of damaged axons to regrow and restore the functional neural circuitry. Coordinated orchestration of multiple cellular processes including cytoskeletal dynamics and gene expression are essential for both developmental and regenerative axon growth. Recently, mounting evidence suggests that Cyclin-Dependent Kinase 5 (Cdk5), a neuronal Kinase implicated in almost all aspects of brain development and function, regulates multiple players required for axon formation and regeneration. Indeed, Cdk5 functions as a “plastic” Kinase that maintains the axon growth ability by enabling efficient cytoskeletal reorganization, enhancing protein translation, reducing protein degradation, and promoting injury-induced gene transcription. Here, we summarize the up-to-date information on the mechanisms underlying the axon growth and regeneration after injury.
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Cyclin-Dependent Kinase 5 (Cdk5)-dependent Phosphorylation of p70 Ribosomal S6 Kinase 1 (S6K) Is Required for Dendritic Spine Morphogenesis.
Journal of Biological Chemistry, 2015Co-Authors: Zhuoyi Liang, Huiqian Huang, Nancy Y. IpAbstract:Abstract The maturation and maintenance of dendritic spines depends on neuronal activity and protein synthesis. One potential mechanism involves mammalian target of rapamycin, which promotes protein synthesis through phosphorylation of eIF4E-binding protein and p70 ribosomal S6 Kinase 1 (S6K). Upon extracellular stimulation, mammalian target of rapamycin phosphorylates S6K at Thr-389. S6K also undergoes phosphorylation at other sites, including four serine residues in the autoinhibitory domain. Despite extensive biochemical studies, the importance of phosphorylation in the autoinhibitory domain in S6K function remains unresolved, and its role has not been explored in the cellular context. Here we demonstrated that S6K in neuron was phosphorylated at Ser-411 within the autoinhibitory domain by Cyclin-Dependent Kinase 5. Ser-411 phosphorylation was regulated by neuronal activity and brain-derived neurotrophic factor (BDNF). Knockdown of S6K in hippocampal neurons by RNAi led to loss of dendritic spines, an effect that mimics neuronal activity blockade by tetrodotoxin. Notably, coexpression of wild type S6K, but not the phospho-deficient S411A mutant, could rescue the spine defects. These findings reveal the importance of Cyclin-Dependent Kinase 5-mediated phosphorylation of S6K at Ser-411 in spine morphogenesis driven by BDNF and neuronal activity.
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Phosphorylation of HtrA2 by Cyclin-Dependent Kinase-5 is important for mitochondrial function
Cell Death & Differentiation, 2011Co-Authors: J. C. Fitzgerald, Nancy Y. Ip, M. D. Camprubi, L. Dunn, H.-c. Wu, Rejko Krüger, L M Martins, Nicholas W. Wood, Helene Plun-favreauAbstract:The role of the serine protease HtrA2 in neuroprotection was initially identified by the demonstration of neurodegeneration in mice lacking HtrA2 expression or function, and the interesting finding that mutations adjacent to two putative phosphorylation sites (S142 and S400) have been found in Parkinson's disease patients. However, the mechanism of this neuroprotection and the signalling pathways associated with it remain mostly unknown. Here we report that Cyclin-Dependent Kinase-5 (Cdk5), a Kinase implicated in the pathogenesis of several neurodegenerative diseases, is responsible for phosphorylating HtrA2 at S400. HtrA2 and Cdk5 interact in human and mouse cell lines and brain, and Cdk5 phosphorylates S400 on HtrA2 in a p38-dependent manner. Phosphorylation of HtrA2 at S400 is involved in maintaining mitochondrial membrane potential under stress conditions and is important for mitochondrial function, conferring cells protection against cellular stress.
Toshio Ohshima - One of the best experts on this subject based on the ideXlab platform.
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Reelin and Cyclin-Dependent Kinase 5
Reelin Glycoprotein, 2020Co-Authors: Toshio OhshimaAbstract:Reelin, an extracellular signaling molecule, and Cyclin-Dependent Kinase 5 (Cdk5), a cytoplasmic Kinase, are key regulators of normal brain development, including establishment of the complex brain structure. Recent studies have indicated that both Reelin signaling and Cdk5 are also involved in synaptic plasticity and neurodegeneration. In this chapter, I shall describe the functions of Cdk5 in neuronal migration during brain development and present an overview of the relationship of Cdk5 with Reelin signaling based on analyses of mutant mouse models. I shall also
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Cyclin-Dependent Kinase 5 (Cdk5) Regulates the Function of CLOCK Protein by Direct Phosphorylation
Journal of Biological Chemistry, 2013Co-Authors: Yongdo Kwak, Toshio Ohshima, Jae Hoon Jeong, Young Un Park, Katsuhiko MikoshibaAbstract:Abstract Circadian rhythm is a biological rhythm governing physiology and behavior with a period of ∼24 h. At the molecular level, circadian output is controlled by a molecular clock composed of positive and negative feedback loops in transcriptional and post-translational processes. CLOCK is a transcription factor known as a central component of the molecular clock feedback loops generating circadian oscillation. Although CLOCK is known to undergo multiple post-translational modifications, the knowledge of their entities remains limited. Cyclin-Dependent Kinase 5 (Cdk5) is a proline-directed serine-threonine Kinase that is involved in various neuronal processes. Here, we report that Cdk5 is a novel regulator of CLOCK protein. Cdk5 phosphorylates CLOCK at the Thr-451 and Thr-461 residues in association with transcriptional activation of CLOCK. The Cdk5-dependent regulation of CLOCK function is mediated by alterations of its stability and subcellular distribution. These results suggest that Cdk5 is a novel regulatory component of the core molecular clock machinery.
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Cyclin-Dependent Kinase 5 is required for normal cerebellar development.
Molecular and Cellular Neuroscience, 2012Co-Authors: A. Kumazawa, Ashok B. Kulkarni, Naoki Mita, Motoyuki Hirasawa, T. Adachi, Hiromi Suzuki, N. Shafeghat, Katsuhiko Mikoshiba, Takafumi Inoue, Toshio OhshimaAbstract:Abstract Cyclin-Dependent Kinase 5 (Cdk5) is a serine/threonine Kinase, and its Kinase activity is dependent upon its association with either of the activating subunits p35 or p39, which are mainly expressed in neurons. We previously reported that Cdk5 knockout (KO) mice exhibit perinatal lethality, defective neuronal migration, and abnormal positioning of neurons in the facial motor nucleus and inferior olive in the hindbrain and Purkinje cells (PCs) in the cerebellum. In this study, we focused on the analysis of the role of Cdk5 in cerebellar development. For this purpose we generated midbrain–hindbrain-specific Cdk5 conditional knockout (MHB-Cdk5 KO) mice because the cerebellum develops postnatally, whereas Cdk5 KO mice die perinatally. Histological analysis of the MHB-Cdk5 KO mice revealed a significant size reduction of the cerebellum. In addition, profound disturbance of inward migration of granule cells (GC) was observed in the developing cerebellum. A normal dendritic development of the Purkinje cells (PCs) was disturbed in MHB-Cdk5 KO mice. Cultured Cdk5-null PCs showed similar dendritic abnormalities. These results indicate that Cdk5/p35 plays an important role in neuronal migration of PCs and GCs and dendrite formation of PCs in cerebellar development.
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Cyclin-Dependent Kinase 5 is required for control of neuroblast migration in the postnatal subventricular zone
The Journal of Neuroscience, 2007Co-Authors: Yuki Hirota, Toshio Ohshima, Ashok B. Kulkarni, Katsuhiko Mikoshiba, Naoko Kaneko, Makiko Ikeda, Takuji Iwasato, Hideyuki Okano, Kazunobu SawamotoAbstract:At the lateral wall of the lateral ventricles in the adult rodent brain, neuroblasts form an extensive network of elongated cell aggregates called chains in the subventricular zone and migrate toward the olfactory bulb. The molecular mechanisms regulating this migration of neuroblasts are essentially unknown. Here, we report a novel role for Cyclin-Dependent Kinase 5 (Cdk5), a neuronal protein Kinase, in this process. Using in vitro and in vivo conditional knock-out experiments, we found that Cdk5 deletion impaired the chain formation, speed, directionality, and leading process extension of the neuroblasts in a cell-autonomous manner. These findings suggest that Cdk5 plays an important role in neuroblast migration in the postnatal subventricular zone.
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Modulation of Reelin signaling by Cyclin-Dependent Kinase 5.
Brain Research, 2006Co-Authors: Toshio Ohshima, Hiromi Suzuki, Toshifumi Morimura, Masaharu Ogawa, Katsuhiko MikoshibaAbstract:Abstract The Reelin signaling and Cyclin-Dependent Kinase 5 (Cdk5) both regulate neuronal positioning in the developing brain. Using double-transgenic mice, we have previously shown that these two signaling pathways lie in parallel fashion and have a genetic interaction. Disabled-1 (Dab1), an adapter protein, mediates Reelin signaling and becomes tyrosine-phosphorylated on the binding of Reelin to its receptors. Several isoforms of Dab1 are expressed in embryonic mouse brain, and p80 [Dab1(555)] is the major protein translated. In the present study, we investigated whether Cdk5-mediated phosphorylation of Dab1 modulates Reelin signaling. Cdk5 phosphorylates p80 Dab1 at multiple sites in its carboxyl-terminal region, and tyrosine phosphorylation of p80 Dab1 by Fyn tyrosine Kinase is attenuated by this Cdk5-mediated phosphorylation in vitro. Tyrosine phosphorylation of p80 Dab1 induced by exogenous Reelin is enhanced in Cdk5-deficient neurons, corroborating the inhibitory effect of Cdk5-mediated Ser/Thr phosphorylation on tyrosine phosphorylation of p80 Dab1. Another isoform, p45 Dab1 [Dab1(271)], however, is phosphorylated by Cdk5 at one serine residue within a unique carboxyl-terminal region, and its serine phosphorylation enhances tyrosine phosphorylation by Fyn and results in progressive degradation of p45 Dab1. These results indicate that Cdk5 modulates Reelin signaling through the Ser/Thr phosphorylation of Dab1 differently in an isoform-specific manner.
