Abstract
Isolated Schwann cells (SCs) respond to cAMP elevation by adopting a differentiated post-mitotic state that exhibits high levels of Krox-20, a transcriptional enhancer of myelination, and mature SC markers such as the myelin lipid galactocerebroside (O1). To address how cAMP controls myelination, we performed a series of cell culture experiments which compared the differentiating responses of isolated and axon-related SCs to cAMP analogs and ascorbate, a known inducer of axon ensheathment, basal lamina formation and myelination. In axon-related SCs, cAMP induced the expression of Krox-20 and O1 without a concomitant increase in the expression of myelin basic protein (MBP) and without promoting axon ensheathment, collagen synthesis or basal lamina assembly. When cAMP was provided together with ascorbate, a dramatic enhancement of MBP expression occurred, indicating that cAMP primes SCs to form myelin only under conditions supportive of basal lamina formation. Experiments using a combination of cell permeable cAMP analogs and type-selective adenylyl cyclase (AC) agonists and antagonists revealed that selective transmembrane AC (tmAC) activation with forskolin was not sufficient for full SC differentiation and that the attainment of an O1 positive state also relied on the activity of the soluble AC (sAC), a bicarbonate sensor that is insensitive to forskolin and GPCR activation. Pharmacological and immunological evidence indicated that SCs expressed sAC and that sAC activity was required for morphological differentiation and the expression of myelin markers such as O1 and protein zero. To conclude, our data indicates that cAMP did not directly drive myelination but rather the transition into an O1 positive state, which is perhaps the most critical cAMP-dependent rate limiting step for the onset of myelination. The temporally restricted role of cAMP in inducing differentiation independently of basal lamina formation provides a clear example of the uncoupling of signals controlling differentiation and myelination in SCs.
Highlights
The formation of a myelin sheath around axons is an exquisite example of the end result of a developmentally regulated highly coordinated cell differentiation process carried out exclusively by two specialized types of glial cells, the oligodendrocyte in the central nervous system and the Schwann cell (SC) in the peripheral nervous system (PNS)
A mechanistic model for the early control of SC differentiation by ACcAMP signals The results presented are consistent with the idea that the adenylyl cyclase (AC)/cyclic adenosine monophosphate (cAMP) signaling system plays a key role in differentiation prior to and possibly independently of the onset of doi:10.1371/journal.pone.0116948.g012
We found that cAMP did not replace the action of ascorbate towards initiating axon ensheathment, basal lamina formation and myelin membrane wrapping
Summary
The formation of a myelin sheath around axons is an exquisite example of the end result of a developmentally regulated highly coordinated cell differentiation process carried out exclusively by two specialized types of glial cells, the oligodendrocyte in the central nervous system and the Schwann cell (SC) in the peripheral nervous system (PNS). In vitro studies of SC myelination suggested that both the ensheathment of axons into one-to-one units and the assembly of a basal lamina on the abaxonal SC surface were required for the formation of a myelin sheath [1]. It was not up until recent years that experiments in animal models allowed the identification of the molecular signals that control myelination through axon contact- and basal lamina-dependent mechanisms, respectively. This balance is illustrated by the cross-antagonistic interplay of signals between Krox-20, a transcriptional enhancer and master regulator of peripheral myelination [5], and c-Jun, a member of the activating protein-1 family of transcription factors whose expression inhibits myelination and induces myelin loss and SC dedifferentiation [6]
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