, 2011). Our results would suggest that the environment that permits NF1−/− cells to differentiate would also need to be acting during normal development to suppress this early signal. Another possibility is that it may indicate that different levels of ERK signaling have opposing effects on the differentiation process. NVP-BEZ235 mw This could be reminiscent of the dual role of neuregulin signaling in the control of Schwann cell myelination and demyelination ( Syed et al., 2010). Consistent with this idea, P-ERK levels are extremely high and are maintained at this high level

for several days in Schwann cells following nerve injury. The inducible, titratable nature of our mouse model may make it a useful system for studying further

how differential activation of this pathway can affect Schwann cell differentiation state in vivo both during development and in the adult. The results of this study also have potential significance for certain peripheral neuropathies, particularly those in which both demyelination and inflammation are observed. Elevated ERK signaling has been implicated in these disorders, making it likely that some aspects of the inflammatory response in these neuropathies are triggered by signals emanating from dedifferentiated Schwann cells (Kohl et al., 2010, Nadra et al., 2008 and Tapinos this website et al., 2006). As these diseases progress, there tends to be increasing axonal damage (Nave, 2010). It is noteworthy that, at least in the short-term, there is no axonal damage associated with either the demyelination or Endonuclease the inflammatory response in the tamoxifen-injected P0-RafTR mouse. This is consistent with the view that Schwann cells provide trophic support to axons irrespective of their differentiation state (Nave, 2010) and that certain injuries can induce focal demyelination without associated axonal injury (Zochodne, 2008). However, it does suggest that the damage to axons seen in the disease states is either the result of a more prolonged response or requires additional factors. In

any case, our findings that the Raf/MEK/ERK signaling pathway drives both the demyelination of peripheral nerves and the associated inflammatory response, together with the observations that recovery takes place when the signal is switched off indicate that inhibitors to this pathway or downstream of this pathway may be useful therapeutics for the treatment of PNS neuropathies and tumors. The RafTR coding sequence was amplified by PCR from the vector pLXSN3-RAFTR using the forward 5′-CATTCCATGGAGTACTCACAGCCG-3′ and reverse primers 5′-CGATGACGTCAGATCGTGTTGGGGAAGC-3′, respectively. The resulting 2.2kb fragment was cloned directly into the AatII site of P0Cx32-Nco-Myc-Aat (A kind gift from Steven Scherer and John Bermingham, Jr.) following removal of the Myc-Tag ATG in the NcoI site.