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We investigated connexin 32 (Cx32)-deficient mice, a model for the X-linked form of Charcot-Marie-Tooth neuropathy (CMT1X), regarding the impact of low-grade inflammation on Schwann cell phenotype. Whereas we previously identified macrophages as amplifiers of the neuropathy, we now explicitly focus on the impact of the phagocytes on Schwann cell dedifferentiation, a so far not-yet addressed disease-related mechanism for CMT1X. Using mice heterozygously deficient for Cx32 and displaying both Cx32-positive and -negative Schwann cells in one and the same nerve, we could demonstrate that macrophage clusters rather than single macrophages precisely associate with mutant but not with Cx32-positive Schwann cells. Similarly, in an advanced stage of Schwann cell perturbation, macrophage clusters were strongly associated with NCAM- and L1-positive, dedifferentiated Schwann cells. To clarify the role of macrophages regarding Schwann cell dedifferentiation, we generated Cx32-deficient mice additionally deficient for the macrophage-directed cytokine colony-stimulating factor (CSF)-1. In the absence of CSF-1, Cx32-deficient Schwann cells not only showed the expected amelioration in myelin preservation but also failed to upregulate the Schwann cell dedifferentiation markers NCAM and L1. Another novel and unexpected finding in the double mutants was the retained activation of ERK signaling, a pathway which is detrimental for Schwann cell homeostasis in myelin mutant models. Our findings demonstrate that increased ERK signaling can be compatible with the maintenance of Schwann cell differentiation and homeostasis in vivo and identifies CSF-1-activated macrophages as crucial mediators of detrimental Schwann cell dedifferentiation in Cx32-deficient mice., (© 2015 Wiley Periodicals, Inc.)

We investigated three models for Charcot-Marie-Tooth type 1 (CMT1) neuropathy, comprising mice lacking connexin 32 (Cx32def), mice with reduced myelin protein zero (P0) expression (P0het) and transgenic mouse mutants overexpressing peripheral myelin protein 22 (PMP22tg), with regard of the expression of the developmentally regulated molecules NCAM, L1, the low-affinity NGF-receptor p75 (p75(NTR) ) and the transcription factor component c-Jun. We found that all molecules were uniformly expressed by myelin deficient and supernumerary Schwann cells. The mutant myelinating Schwann cells of PMP22tg mice showed a robust NCAM-immunoreactivity in Schmidt-Lanterman incisures (SLI) that accompanies other early onset abnormalities, such as the presence of supernumerary Schwann cells and impaired myelin formation in some fibers. In line with this, Cx32def and P0het mice, which represent demyelinating models, only rarely express NCAM in SLI. Surprisingly, c-Jun immunoreactivity displayed a mosaic-like pattern with mostly negative and some weakly or moderately positive nuclei both in myelinating Schwann cells and Remak cells of wildtype (wt), P0het and PMP22tg mice. However, c-Jun expression was substantially upregulated in myelinating Schwann cells of Cx32def mice and spatially associated with axon perturbation, a typical predemyelinating feature of Cx32 deficiency. Additionally, c-Jun upregulation was correlated with an elevated level of GDNF, possibly causally linked to the typical compensatory sprouting of axons in Cx32def mice and CMT1X patients. Our findings suggest that in myelinating Schwann cells of distinct models of CMT1, c-Jun upregulation is a marker for predemyelinating axonal perturbation while myelin-related NCAM expression is indicative for early Schwann cell abnormalities., (Copyright © 2014 Wiley Periodicals, Inc.)