p39, the Primary Activator for Cyclin-dependent Kinase 5 (Cdk5) in Oligodendroglia, Is Essential for Oligodendroglia Differentiation and Myelin Repair

Bankston, Andrew N.; Li, Wenqi; Zhang, Hui; Ku, Li; Liu, Guanglu; Papa, Filomena; Zhao, Lixia; Bibb, James A.; Cambi, Franca; Tiwari‐Woodruff, Seema K.; Feng, Yue

doi:10.1074/jbc.m113.453688

Cited by 14 publications

(10 citation statements)

References 55 publications

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“…P39 is the principal Cdk5 activator in oligodendroglia and is required for myelin repair and oligodendroglial differentiation [30]. Cdk5/p39 is also responsible for Munc18-1 phosphorylation during Ca ++ -induced insulin exocytosis [31] and phosphorylates the microtubule protein tau in the developing mouse brain [31].…”

Section: Discussionmentioning

confidence: 99%

The Cdk5 activator P39 specifically links muskelin to myosin II and regulates stress fiber formation and actin organization in lens

Tripathi

Lowy

Zelenka

2015

Experimental Cell Research

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Cyclin dependent kinase 5 (Cdk5), a proline-directed serine/threonine kinase, requires p39 for its enzymatic activity, and is implicated in cytoskeletal organization and contraction in numerous cell types. The C-terminus of p39 binds muskelin, a multi-domain scaffolding protein known to affect cytoskeletal organization, but the mechanism(s) by which muskelin affects cytoskeletal organization remain unclear. The present study sought to determine whether p39 might serve as an adaptor protein that links muskelin to stress fibers and to investigate the possible biological relevance of such an interaction. Double immunoprecipitation showed that muskelin, p39, and myosin II are components of a single intracellular complex, and suppressing p39 abrogated the interaction between muskelin and the myosin subunits, demonstrating that p39 is required to link muskelin to myosin II. Muskelin is colocalized with myosin regulatory light chain (MRLC) and on stress fibers. The suppression of muskelin reduced Rho-GTP, MRLC phosphorylation, disrupted stress fiber organization, and promoted cell migration, all of which closely mimics the effect of Cdk5 inhibition. Moreover, suppressing muskelin and inhibiting Cdk5 together has no additional effect, indicating that muskelin plays an important role in Cdk5-dependent signaling. P39 is necessary and sufficient for Cdk5-dependent regulation of MRLC phosphorylation, as suppression of p39, but not p35, reduced MRLC phosphorylation. Together, these results demonstrate that p39 specifically links muskelin to myosin II and consequently, to stress fibers and reveal a novel role for muskelin in regulating myosin phosphorylation and cytoskeletal organization.

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Section: Discussionmentioning

confidence: 99%

The Cdk5 activator P39 specifically links muskelin to myosin II and regulates stress fiber formation and actin organization in lens

Tripathi

Lowy

Zelenka

2015

Experimental Cell Research

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“…The expression of p39, but not p35, is upregulated during remyelinization and is essential for the repair of myelin lesions. 21 In addition, both regulatory subunits also have different abilities to phosphorylate tau, but only Cdk5/p39 is involved in the in vivo phosphorylation of tau at Ser-202 and Thr-205 during brain development. 12 Discrete-specific roles for both activators have been demonstrated in nonneuronal cells as well.…”

Section: Discussionmentioning

confidence: 99%

“…Even though p35 −/− mice are viable and fertile, they display subtle impaired neuronal migration and inverted neuronal layering in the cerebral cortex along with abnormal hippocampus morphology. 19 In contrast, mice lacking p39 have no obvious phenotypic defects or apparent abnormalities 20 but show impaired remyelination 21 and exhibit defects in axonal growth and dendritic spine formation. 22 Compound deletion of both Cdk5 activators results in perinatal lethality 20 and a phenotype that is nearly identical to the Cdk5 −/− mice, 6 which suggests that both p35 and p39 are major activators of Cdk5 that contribute to in vivo activation of Cdk5 in a region-specific and developmentally regulated manner.…”

Section: Introductionmentioning

confidence: 99%

Peripheral and orofacial pain sensation is unaffected by the loss of p39

Procházková

Hall

et al. 2017

Mol Pain

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Cdk5 is a key neuronal kinase necessary for proper brain development, which has recently been implicated in modulating nociception. Conditional deletion of Cdk5 in pain-sensing neurons attenuates pain responses to heat in both the periphery and orofacial regions. Cdk5 activity is regulated by binding to the activators p35 and p39, both of which possess a cyclin box. Our previous examination of the nociceptive role of the well-characterized Cdk5 activator p35 using mice that either lack or overexpress this regulatory subunit demonstrated that Cdk5/p35 activity affects mechanical, chemical, and thermal nociception. In contrast, the nociceptive role of Cdk5’s other less-studied activator p39 is unknown. Here, we report that the knockout of p39 in mice did not affect orofacial and peripheral nociception. The lack of any algesic response to nociceptive stimuli in the p39 knockout mice contrasts with the hypoalgesic effects that result from the deletion of p35. Our data demonstrate different and nonoverlapping roles of Cdk5 activators in the regulation of orofacial as well as peripheral nociception with a crucial role for Cdk5/p35 in pain signaling.

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“…Understanding possible glial migrational roles of Cdk5 in nestin-lineage progenitors would reveal common or divergent roles for this regulator in neurons vs. glial cells, similar to what has been found using in vivo [19,20,73] and in vitro [26–28] migrational assays. Future experiments examining the role of Cdk5 in early postnatal glial migration of nestin-expressing progenitors as well as the biochemical and molecular underpinnings of its role would therefore require separate, comprehensive study employing in vivo , in vitro , and ex vivo strategies [20,62,74–79]. It is also possible that in addition to impaired proliferation, differentiation/maturation, and migration, early deficits in the nestin-expressing progenitors may contribute to the iCdk5 phenotype.…”

Section: Discussionmentioning

confidence: 99%

Early Postnatal In Vivo Gliogenesis From Nestin-Lineage Progenitors Requires Cdk5

et al. 2013

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The early postnatal period is a unique time of brain development, as diminishing amounts of neurogenesis coexist with waves of gliogenesis. Understanding the molecular regulation of early postnatal gliogenesis may provide clues to normal and pathological embryonic brain ontogeny, particularly in regards to the development of astrocytes and oligodendrocytes. Cyclin dependent kinase 5 (Cdk5) contributes to neuronal migration and cell cycle control during embryogenesis, and to the differentiation of neurons and oligodendrocytes during adulthood. However, Cdk5’s function in the postnatal period and within discrete progenitor lineages is unknown. Therefore, we selectively removed Cdk5 from nestin-expressing cells and their progeny by giving transgenic mice (nestin-CreERT2/R26R-YFP/CDK5flox/flox [iCdk5] and nestin-CreERT2/R26R-YFP/CDK5wt/wt [WT]) tamoxifen during postnatal (P) days P2-P 4 or P7-P 9, and quantified and phenotyped recombined (YFP+) cells at P14 and P21. When Cdk5 gene deletion was induced in nestin-expressing cells and their progeny during the wave of cortical and hippocampal gliogenesis (P2-P4), significantly fewer YFP+ cells were evident in the cortex, corpus callosum, and hippocampus. Phenotypic analysis revealed the cortical decrease was due to fewer YFP+ astrocytes and oligodendrocytes, with a slightly earlier influence seen in oligodendrocytes vs. astrocytes. This effect on cortical gliogenesis was accompanied by a decrease in YFP+ proliferative cells, but not increased cell death. The role of Cdk5 in gliogenesis appeared specific to the early postnatal period, as induction of recombination at a later postnatal period (P7-P9) resulted in no change YFP+ cell number in the cortex or hippocampus. Thus, glial cells that originate from nestin-expressing cells and their progeny require Cdk5 for proper development during the early postnatal period.

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p39, the Primary Activator for Cyclin-dependent Kinase 5 (Cdk5) in Oligodendroglia, Is Essential for Oligodendroglia Differentiation and Myelin Repair

Cited by 14 publications

References 55 publications

The Cdk5 activator P39 specifically links muskelin to myosin II and regulates stress fiber formation and actin organization in lens

The Cdk5 activator P39 specifically links muskelin to myosin II and regulates stress fiber formation and actin organization in lens

Peripheral and orofacial pain sensation is unaffected by the loss of p39

Early Postnatal In Vivo Gliogenesis From Nestin-Lineage Progenitors Requires Cdk5

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