Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death.

Ohshima, Toshio; Ward, Jerrold M.; Huh, Chang Goo; Longenecker, Glenn; Veeranna,; Pant, Harish C.; Brady, Roscoe O.; Martin, Lee J.; Kulkarni, Ashok B.

doi:10.1073/pnas.93.20.11173

Cited by 855 publications

(781 citation statements)

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“…Furthermore, Ckd5 can directly phosphorylate the microtubule-binding protein Doublecortin to mediate nuclear translocation during post-mitotic cell migration (Tanaka et al, 2004). Consistent with these results, deletion of cdk5 in mice results in lamination defects in the CNS (Ohshima et al, 1996). However, the in vivo role for Fak in nuclear migration, appears to be more complicated.…”

Section: Kinases In Nuclear Migrationmentioning

confidence: 55%

Nuclear migration during retinal development

2008

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In this review we focus on the mechanisms, regulation, and cellular consequences of nuclear migration in the developing retina. In the nervous system, nuclear migration is prominent during both proliferative and post-mitotic phases of development. Interkinetic nuclear migration is the process where the nucleus oscillates from the apical to basal surfaces in proliferative neuroepithelia. Proliferative nuclear movement occurs in step with the cell cycle, with M-phase being confined to the apical surface and G1-, S-, and G2-phases occurring at more basal locations. Later, following cell cycle exit, some neuron precursors migrate by nuclear translocation. In this mode of cellular migration, nuclear movement is the driving force for motility. Following discussion of the key components and important regulators for each of these processes, we present an emerging model where interkinetic nuclear migration functions to distinguish cell fates among retinal neuroepithelia. Keywordsinterkinetic nuclear migration; nuclear translocation; nucleokinesis; neurogenesis; dynein; cell cycle; cell behavior OverviewNeuronal development is regulated by a complex array of intrinsic and extrinsic signals that act on progenitor neuroepithelial cells to ensure the correct cell type is generated in the right numbers and at the appropriate time of development (Donovan et al., 2005;Cayouette et al., 2006). In addition, multiple signaling cues are integrated in post-mitotic neuronal precursors to facilitate directed cell migration and correct laminar positioning (Malicki et al., 2004). This spatial and temporal regulation of neuronal cell-type fate commitment and histogenesis is dependent on the regulation of the mitotic cell cycle, and in particular at the level of cell cycle exit (Ohnuma and Harris, 2003). Recent data suggest that nuclear migration is a critical process for several aspects of neuronal development, including that of the neural retina. The focus of this review is on interkinetic nuclear migration and nuclear translocation during retinogenesis, although much of what we know is from observations in other regions of the developing nervous system. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript Interkinetic nuclear migrationInterkinetic nuclear migration is the proliferative cell behavior where the nuclei of neuroepithelial cells migrate in an apical-basal manner and in phase with the cell cycle (Frade 2002). Neuroepithelial cell divisions are confined to apical locations while S-phase occu...

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Section: Kinases In Nuclear Migrationmentioning

confidence: 55%

Nuclear migration during retinal development

2008

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“…Moreover, p35⅐Cdk5 appears to be important for normal neuronal function; its kinase activity increases during neurogenesis, and it is essential for neurite outgrowth during neuronal differentiation (11). A fundamental role for p35⅐Cdk5 is supported by the findings that targeted disruption of the p35 gene in the mouse leads to severe defects in laminar organization of neurons in the neocortex and cerebellum, 2 and targeted disruption of Cdk5 gene leads to abnormal corticogenesis, lesions in the central nervous system, and perinatal death (29). Although p35 shares little sequence similarity to cyclin, computer modeling predicts that p35 may fold into cyclin-like tertiary structure and activate Cdk5 in a manner similar to a cyclin (30).…”

mentioning

confidence: 63%

“…If Cdk5 function is important for neuronal differentiation, as indicated by recent evidence (11,29), then Cdk5 must be regulated by very different mechanisms compared with other cell cycle-regulating cyclin⅐CDK complexes. Cell cycle-regulating cyclins and CDKs are generally turned off during neuronal differentiation (51,52), since cell cycle arrest appears to be a prerequisite for differentiation.…”

Section: Discussionmentioning

confidence: 99%

Identification of Functional Domains in the Neuronal Cdk5 Activator Protein

Poon

Lew

Hunter

1997

Journal of Biological Chemistry

102

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Cyclin-dependent kinase 5 (Cdk5) is activated by the neuronal-specific activator protein, p35. In contrast to the activation of typical CDKs by cyclin subunits, p35⅐Cdk5 was not further activated by the CDK-activating kinase (CAK) and was neither phosphorylated nor inhibited by the Tyr-15-specific Wee1 kinase. The previously identified proteolytic active fragment of p35, p25 (residues 91-307) as well as the slightly smaller fragment containing residues 109 -291, was found to be sufficient to bind and activate Cdk5. Other CDKs, including Cdk2, associated weakly with p25. However, their kinase activity was only activated to the low level observed for cyclin A⅐Cdk2 without Thr-160 phosphorylation, and phosphorylation of Thr-160 in Cdk2 did not activate the p25⅐Cdk2 complex further. We have identified distinct regions in p35 required for binding to Cdk5 or activation of Cdk5. Residues ϳ150 -200 of p35 were sufficient for binding to Cdk5, but residues ϳ279 -291 were needed in addition for activation of Cdk5 in vitro.Cyclins and cyclin-dependent kinases (CDKs) 1 are key regulators of the eukaryotic cell cycle (1). Cdc2 is associated with B-type cyclins and regulates M phase (2). Cdk2 is associated with A-and E-type cyclins, and the respective complexes are believed to control the S phase and G 1 -S transition, respectively (3, 4). Cdk4 and Cdk6 are associated with the D-type cyclins and are important for G 1 progression (3).The activity of CDKs is tightly regulated by an intricate system of protein-protein interaction and phosphorylation (5). The activation of CDKs, by definition, requires the association with cyclin partners. Full activation of CDKs requires in addition the phosphorylation of Thr-161/Thr-160, which lies in the activating T-loop in the crystal structure of Cdk2 (6, 7). The Thr-161/Thr-160 residue is phosphorylated by the CDK-activating kinase (CAK), which is composed of a cyclin H-Cdk7 complex and a RING finger protein subunit MAT1 (8). The activity of CDKs can be inhibited by phosphorylation of Thr-14 and Tyr-15 by the Wee1 and Myt1 protein kinases (9). Furthermore, CDKs can be inactivated by binding to CDK inhibitors like those from the p21 cip1/WAF1 family (p21 cip1/WAF1 , p27 kip1 , and p57 kip2 ) and the p16 INK4A family (p16 INK4A , p15 INK4B

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“…25,34 Cdk5 function is crucial in cortical development as mice lacking this serine/threonine kinase or its neuronal activator p35 display inverted layering of neurons. [36][37][38][39][40] A series of experiments demonstrated that NUDEL is likely to be a physiological substrate of Cdk5. 34 Thus it may form a link between a Cdk5 and a LIS1-mediated neuronal migration pathway.…”

Section: Nude and Nudelmentioning

confidence: 99%