Myelin‐associated glycoprotein modulates expression and phosphorylation of neuronal cytoskeletal elements and their associated kinases

Abstract

Decreased phosphorylation of neurofilaments in mice lacking myelin-associated glycoprotein (MAG) was shown to be associated with decreased activities of extracellular-signal regulated kinases (ERK1/2) and cyclin-dependent kinase-5 (cdk5). These in vivo changes could be caused directly by the absence of a MAG-mediated signaling pathway or secondary to a general disruption of the Schwann cell-axon junction that prevents signaling by other molecules. Therefore, in vitro experimental paradigms of MAG interaction with neurons were used to determine if MAG directly influences expression and phosphorylation of cytoskeletal proteins and their associated kinases. COS-7 cells stably transfected with MAG or with empty vector were co-cultured with primary dorsal root ganglion (DRG) neurons. Total amounts of the middle molecular weight neurofilament subunit (NF-M), microtubule-associated protein 1B (MAP1B), MAP2, and tau were up-regulated significantly in DRG neurons in the presence of MAG. There was also increased expression of phosphorylated high molecular weight neurofilament subunit (NF-H), NF-M, and MAP1B. Additionally, in similar in vitro paradigms, total and phosphorylated NF-M were increased significantly in PC12 neurons co-cultured with MAG-expressing COS cells or treated with a soluble MAG Fc-chimera. The increased expression of phosphorylated cytoskeletal proteins in the presence of MAG in vitro was associated with increased activities of ERK 1/2 and cdk5. We propose that interaction of MAG with an axonal receptor(s) induces a signal transduction cascade that regulates expression of cytoskeletal proteins and their phosphorylation by these proline-directed protein kinases.

Rap1 is involved in the signal transduction of myelin-associated glycoprotein

“…Furthermore, TAT-Rap1A DA did not mimic the effect of MAG-Fc (Supplementary Figure 5S). As shown previously, 21 addition of MAG-Fc activated extracellular signal-regulated kinases (ERKs) in the CGNs. However, transduction of TAT-Rap1A DN did not modulate the ERKs phosphorylation induced by MAG-Fc (Supplementary Figure 6S), although ERK activation has been implicated in MAG-induced growth inhibition.…”

Dramatic Reduction of PrPCLevel and Glycosylation in Peripheral Nerves following PrP Knock-Out from Schwann Cells Does Not Prevent Transmissible Spongiform Encephalopathy Neuroinvasion

“…This finding was consistently observed in all adult Schwann cell PrP knock-out mice investigated with ages ranging from 21 to 700 d old. The knock-out of PrP in this model likely occurs during embryonic development and the regulation of axonal protein expression and processing by Schwann cell glycoproteins has been shown previously (Dashiell et al, 2002); therefore we cannot rule out the possibility that removal of PrP expression from Schwann cells may affect PrP expression in associated nerve axons.…”

Neurofilaments at a glance

“…Myelination has an effect on NF phosphorylation. This is evidenced by the observations that NF phosphorylation is decreased in dysmyelinating mutant Trembler mice (de Waegh et al, 1992) and at the initial segment of optic nerves and nodes of Ranvier (the gaps formed between the myelin sheaths generated by different cells) (Hsieh et al, 1994;Mata et al, 1992;Reles and Friede, 1991), as well as by the possible role of myelin associated glycoprotein (MAG) as a mediator of myelin signals that alter NF phosphorylation (Dashiell et al, 2002;Yin et al, 1998). Phosphorylation of the tail domain can regulate both the interactions between the NF domains themselves and with microtubules (Hisanaga and Hirokawa, 1989;Hisanaga et al, 1991).…”