Activation of the transcription factor NF-κB in Schwann cells is required for peripheral myelin formation

Abstract

Peripheral myelin formation is initiated by axonal cues that trigger a differentiation program in associated Schwann cells. Here, we define one essential differentiation signal: activation of the transcription factor NF-kappaB. In rat sciatic nerves, NF-kappaB was highly upregulated in pre-myelinating Schwann cells, and then its expression progressively declined until it was nearly absent in adults. Similarly, in co-cultures of Schwann cells and sensory neurons, NF-kappaB activation paralleled myelination, and blocking its activity or using cells from mice lacking the NF-kappaB subunit p65 markedly attenuated myelination. Inhibiting NF-kappaB also prevented activation of Oct-6, a transcription factor induced by axonal contact and required for proper myelin formation. These results show that the activation of NF-kappaB is an essential signal for the progression of axon-associated Schwann cells into a myelinating phenotype.

Axonal Neuregulin 1 Type III Activates NF-κB in Schwann Cells during Myelin Formation

“…Myelinating DRG/Schwann cell co-cultures were established using DRGs isolated from E15 rats as described (1,5) and plated in Ultraculture media (BioWhittaker) supplemented with 10% FBS (HyClone), 2 mM L-glutamine (Invitrogen), and 50 ng/ml NGF (Harlan) at a density of 80,000 cells/2.2 cm 2 collagencoated coverslip. Myelination was induced 5 days later by adding 50 g/ml ascorbic acid in growth media.…”

“…NF-B is active in the sciatic nerve during peripheral myelin formation and in myelinating dorsal root ganglia (DRG) 2 /Schwann cell co-cultures. Furthermore, myelination in the co-cultures was prevented by blocking the transcription factor or by genetic deletion of the p65 subunit of NF-B (1). These data indicate that NF-B activation in Schwann cells is a critical event for their differentiation into a myelinating phenotype; however, the mechanism by which axons stimulate the transcription factor remains to be elucidated.…”

“…Cells-Schwann cells in the perinatal sciatic nerve as well as in culture with DRG neurons in vitro display activated NF-B, and this signal was necessary for myelin formation (1,5). Because myelination requires axonally derived signals, we hypothesized that axonal contact is responsible for activating NF-B.…”

Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

“…These are important in immature Schwann cells for the correct timing of myelination, and in addition, Sox-10, which besides its importance for the generation of Schwann cell precursors (SCPs), is required for Oct-6 expression in immature Schwann cells and the activation of myelin genes (Bermingham et al, 1996;Britsch et al, 2001;Jaegle et al, 1996;Schreiner et al, 2007) [reviewed in (Jessen and Mirsky, 2005;Topilko and Meijer, 2001)]. In vitro experiments indicate that the myelination machinery also includes the transcription factor NFjB and that this factor may act as a mediator of cyclic AMP (cAMP) signaling (below) (Nickols et al, 2003;Yoon et al, 2008). cAMP has long been known to activate myelin genes and mimic many of the effects of axonal myelin signals in isolated Schwann cells in vitro (Lemke and Chao, 1988;Morgan et al, 1991).…”

Retinoid-induced activation of NF-κB in APL cells is not essential for granulocytic differentiation, but prolongs the life span of mature cells

“…NF-kB pathway is also involved in the regulation of differentiation in many different systems, including mammalian skin, neuronal cells, osteoclasts, myoblasts, and the innate and adaptive immune systems (Iotsova et al, 1997;Bell et al, 2003;Nickols et al, 2003;Bonizzi and Karin, 2004). In addition, analysis of NF-kBdeficient mice and cells identified this transcription factor as a major determinant of cell survival (Karin and Lin, 2002;Kucharczak et al, 2003) and sensitivity of cancers to chemotherapy (Orlowski and Baldwin, 2002).…”