The Second Messenger, Cyclic AMP, Is Not Sufficient for Myelin Gene Induction in the Peripheral Nervous System

Abstract

The adenylyl cyclase‐cyclic AMP (cAMP) second messenger pathway has been proposed to regulate myelin gene expression; however, a clear correlation between endogenous cAMP levels and myelin‐specific mRNA levels has never been demonstrated during the induction or maintenance of differentiation by the myelinating Schwann cell. Endogenous cAMP levels decreased to 8–10% of normal nerve by 3 days after crush or permanent transection injury of adult rat sciatic nerve. Whereas levels remained low after transection injury, cAMP levels reached only 27% of the normal values by 35 days after crush injury. Because P0 mRNA levels were 60% of normal levels by 14 days and 100% by 21 days after crush injury, cAMP increased only well after P0 gene induction. cAMP, therefore, does not appear to trigger myelin gene induction but may be involved in myelin assembly or maintenance. Forskolin, an activator of adenylyl cyclase, increased endoneurial cAMP levels only in the normal nerve, and in the crushed nerve beginning at 16 days after injury, but at no time in the transected nerve. Only by treating transected nerve with 3‐isobutyl‐1‐methylxanthine (IBMX), an inhibitor of cAMP phosphodiesterases, in combination with forskolin was it possible to increase cAMP levels. No induction of myelin genes, however, was observed with short‐ or long‐term treatment with IBMX and forskolin in the transected nerve. A three‐fold increase in phosphodiesterase activity was observed at 35 days after both injuries, and a nonmyelinated nerve was shown to have even higher activity. These experiments, therefore, suggest an important role for phosphodiesterase in the inactivation of this second messenger‐dependent stimuli when Schwann cells are non‐myelinating, such as after sciatic nerve injury or in the nonmyelinated nerve, which again implies that cAMP may be required for the maintenance of the myelin sheath.

E‐cadherin expression in postnatal Schwann cells is regulated by the cAMP‐dependent protein kinase a pathway

“…This is evident by previous studies, which have shown that cAMP in rat sciatic nerve increases during nerve regeneration and decreases following nerve injury (Poduslo et al 1995; Walikonis et al 1998). Furthermore, it has been shown that there is a high endogenous cAMP level in myelinated nerve, but not in non-myelinated nerve, hence associating cAMP elevation with building of the myelin sheath (Poduslo et al 1995). Therefore, developmental regulation of endogenous cAMP might be associated with the cAMP-dependent axonal function that regulates postnatal development of myelinating Schwann cell lineage in the PNS.…”

Schwann Cell Dedifferentiation Is Independent of Mitogenic Signaling and Uncoupled to Proliferation

“…However, more direct evidence was provided recently with the discovery of a novel G-protein-coupled receptor that is required for SC myelination in zebrafish and that it does so in a cAMP-dependent manner (47). We can therefore speculate that dedifferentiation and/or myelin loss may simply result from a reduction of cAMP in SCs, as those observed after injury (48). In support of this, we show that a reduction of intracellular cAMP is sufficient to trigger a dedifferentiating signal that directly impinges on the early transcriptional control of myelin gene expression.…”

Modification of representational difference analysis applied to the isolation of forskolin‐regulated genes from Schwann cells

“…However, the role of cAMP signaling in regulating the phenotype of Schwann cells is complex. Although forskolin can promote both proliferation and differentiation in cultured Schwann cells, in injured nerves, intracellular cAMP levels rise after reexpression of P0, and increasing the concentration of intracellular cAMP does not induce myelin gene expression (Poduslo et al, 1995). The identification of additional genes that are regulated by forskolin in Schwann cells would thus enhance our understanding of the functions of cAMP signaling in Schwann cell differentiation.…”