Changes in the activity of cdk2 and cdk5 accompany differentiation of rat primary oligodendrocytes

Abstract

Oligodendrocytes, the myelinating cells of the central nervous system, are terminally differentiated cells that originate through asynchronous waves of proliferation and differentiation of precursors present at birth. Withdrawal from cell cycle and onset of differentiation are tightly linked and depend on an intrinsic program modulated by the action of growth factors. p27 plays a central and obligatory role in the initiation of oligodendrocyte differentiation and cessation of proliferation. In this paper, we have characterized the role of modulation of cdk2 and cdk5 kinase activity during the process of oligodendrocyte precursor differentiation. As rat primary oligodendrocytes differentiate in culture there is a fall in cdk2 activity and a rise in cdk5 activity as well as an increase in the cdk inhibitor, p27 protein. The decline in cdk2 activity is not accompanied by a drop in cdk2 protein level, suggesting that it results from inhibition of cdk2 activation rather than decreased protein expression. Taken together, these data suggest that oligodendrocytes may withdraw from the cell cycle at G1-S transition through inactivation of cdk2 activity, possibly initiated by increasing amount of p27, and that cdk5 may have a role until now unrecognized in the differentiation of oligodendrocytes.

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

“…3D). Thus, the developmentally programmed up-regulation of p39 mRNA leads to increased production of p39 protein, which underlies the increase of Cdk5 activity during OL and myelin development reported by previous studies (11,12).…”

“…We show for the first time that OLs primarily express p39 for Cdk5 activation, with scarce levels of p35. Moreover, the selective upregulation of p39, but not p35, during OL differentiation in culture and in vivo clearly demonstrated that p39 is responsible for the increased Cdk5 activity during OL differentiation (11,12). Given the fact that the most rigorous OL development occurs in the first few postnatal weeks (14), OL-produced p39 must be an important contributor to the previously reported preferential increase of p39 during neonatal brain development (26).…”

“…p39, but Not p35, Is Up-regulated during OL and Myelin Development-During OL differentiation, Cdk5 activity is markedly up-regulated (11,12). To explore which activator is responsible for the enhanced Cdk5 activity, we analyzed the expression levels of Cdk5 and its activators during OL differen- Ϫ/Ϫ brain, primary cultured rat neurons (N), astrocytes (A), OLs, and CG4 cells were subjected to immunoblot analysis of p39, p35, Cdk5, and eIF5␣.…”

“…Earlier studies demonstrated essential functions of Cdk5 in neuronal migration, neural network formation, and synaptic plasticity in mammalian brains (5). Besides the traditional view of neuronal centric roles of Cdk5, emerging evidence suggests that Cdk5 also governs the development of oligodendroglia progenitor cells (OPCs) (11)(12)(13). Similar to brain neurons, OPCs migrate to distant brain areas and become mature OLs to myelinate neuronal axons (14).…”

Exercise decreases myelin‐associated glycoprotein expression in the spinal cord and positively modulates neuronal growth

“…Cyclin-Dependent Kinase (cdk) 5-associated activity was measured as previously reported (Ghiani and Gallo, 2001;Tang et al, 1998;Tsai et al, 1993). Cells or tissues were lysed in 50 mM HEPES, pH 7.4, 250 mM NaCl, 5 mM EDTA, 0.5% NP-40, 10% Na 4 P 2 O 4 ,1 mM Na 3 VO 4 , 4 mM NaF, 10 mg/mL leupeptin, 10 mg/mL aprotinin, 10 mg/mL pepstatin, and 1 mM AEBSF.…”