Schwann cell myelination depends on Krox-20/Egr2 and other promyelin transcription factors that are activated by axonal signals and control the generation of myelin-forming cells. Myelin-forming cells remain remarkably plastic and can revert to the immature phenotype, a process which is seen in injured nerves and demyelinating neuropathies. We report that c-Jun is an important regulator of this plasticity. At physiological levels, c-Jun inhibits myelin gene activation by Krox-20 or cyclic adenosine monophosphate. c-Jun also drives myelinating cells back to the immature state in transected nerves in vivo. Enforced c-Jun expression inhibits myelination in cocultures. Furthermore, c-Jun and Krox-20 show a cross-antagonistic functional relationship. c-Jun therefore negatively regulates the myelinating Schwann cell phenotype, representing a signal that functionally stands in opposition to the promyelin transcription factors. Negative regulation of myelination is likely to have significant implications for three areas of Schwann cell biology: the molecular analysis of plasticity, demyelinating pathologies, and the response of peripheral nerves to injury.

In dystrophic mice, a model of merosin‐deficient congenital muscular dystrophy, laminin‐2 mutations produce peripheral nerve dysmyelination and render Schwann cells unable to sort bundles of axons. The laminin receptor and the mechanism through which dysmyelination and impaired sorting occur are unknown. We describe mice in which Schwann cell‐specific disruption of beta1 integrin, a component of laminin receptors, causes a severe neuropathy with impaired radial sorting of axons. Beta1‐null Schwann cells populate nerves, proliferate, and survive normally, but do not extend or maintain normal processes around axons. Interestingly, some Schwann cells surpass this problem to form normal myelin, possibly due to the presence of other laminin receptors such as dystroglycan and α6β4 integrin. These data suggest that PI integrin links laminin in the basal lamina to the cytoskeleton in order for Schwann cells to ensheath axons, and alteration of this linkage contributes to the peripheral neuropathy of congenital muscular dystrophy.

lipid metabolism ͉ neuron-glia interactions ͉ neuropathy ͉ X-ray diffraction T he rapid saltatory conduction of neuronal action potentials is crucially dependent on the insulating myelin membrane, an organelle synthesized by Schwann cells in the PNS, and by oligodendrocytes in the CNS (1). The electrical insulating property of the myelin membrane is provided by its high and characteristic lipid content with high levels of cholesterol, galactosphingolipids, and saturated long-chain fatty acids (1). Accordingly, metabolic disorders of cholesterol [e.g., Smith-Lemli-Opitz-syndrome and Tangier disease (2, 3)], galactosphingolipids (4, 5), or of fatty acid metabolism [Refsum's disease and diabetes mellitus (2)] often produce myelin defects.With the Schwann cell membrane surface area expanding a spectacular 6,500-fold during myelination (6), it is obvious that production of myelin membrane requires a large amount and diversity of myelin proteins and lipids. Myelination of peripheral nerves is a highly dynamic process with an acute phase that peaks in the second postnatal week in the mouse and a phase of steady-state maintenance in adult nerves (7). While it has been suggested that many of the myelin lipids are synthesized in the nerve itself, as was demonstrated for cholesterol (8, 9), the factors regulating their synthesis in myelinating Schwann cells are largely unknown. We recently profiled transcription in the peripheral nerve during myelination and found that sterol regulatory elementbinding proteins (SREBPs) are highly expressed in myelinating Schwann cells (10)(11)(12). SREBPs, consisting of SREBP-1a, SREBP1c, and SREBP-2, belong to the family of basic helix-loop-helixleucine zipper (bHLH-Zip) transcription factors that regulate lipid metabolism. SREBP-1c and SREBP-2 preferentially govern the transcriptional activation of genes involved in fatty acid and cholesterol metabolism, respectively, whereas SREBP-1a activates both pathways (13). SREBP transcription factors crucially rely on post-translational activation involving the sterol sensor SCAP. When sterol levels are low, SCAP escorts the SREBPs from the ER to the Golgi, where they are activated by processing through the membrane-associated proteases, S1P and S2P. The resulting mature and transcriptionally active forms of the SREBPs translocate to the nucleus where they bind genes containing sterol regulatory elements (13,14).Here, we determined the role of SCAP in myelination by its conditional ablation in Schwann cells. We found that deletion of SCAP seriously affected the dynamics of myelin membrane synthesis and caused neuropathy. However, these phenotypes improved with aging; SCAP mutant Schwann cells were able to slowly synthesize myelin, in an external lipid-dependent fashion, resulting in myelin membrane defects that are associated with abnormal lipid composition. Our data demonstrated the crucial role of SCAPmediated control of cholesterol and lipid metabolism necessary for production of a proper myelin membrane by Schwann cells.

Peripheral neuropathies often result in abnormalities in the structure of internodal myelin, including changes in period and membrane packing, as observed by electron microscopy (EM). Mutations in the gene that encodes the major adhesive structural protein of internodal myelin in the peripheral nervous system of humans and mice--P0 glycoprotein--correlate with these defects. The mechanisms by which P0 mutations interfere with myelin packing and stability are not well understood and cannot be provided by EM studies that give static and qualitative information on fixed material. To gain insights into the pathogenesis of mutant P0, we used x-ray diffraction, which can detect more subtle and dynamic changes in native myelin, to investigate myelin structure in sciatic nerves from murine models of hereditary neuropathies. We used mice with disruption of one or both copies of the P0 gene (models of Charcot-Marie-Tooth-like neuropathy [CMT1B] or Dejerine-Sottas-like neuropathy) and mice with a CMT1B resulting from a transgene encoding P0 with an amino terminal myc-tag. To directly test the structural role of P0, we also examined a mouse that expresses P0 instead of proteolipid protein in central nervous system myelin. To link our findings on unfixed nerves with EM results, we analyzed x-ray patterns from unembedded, aldehyde-fixed nerves and from plastic-embedded nerves. From the x-ray patterns recorded from whole nerves, we assessed the amount of myelin and its quality (i.e. relative thickness and regularity). Among sciatic nerves having different levels of P0, we found that unfixed nerves and, to a lesser extent, fixed but unembedded nerves gave diffraction patterns of sufficient quality to distinguish periods, sometimes differing by a few Angstroms. Certain packing abnormalities were preserved qualitatively by aldehyde fixation, and the relative amount and structural integrity of myelin among nerves could be distinguished. Measurements from the same nerve over time showed that the amount of P0 affected myelin's stability against swelling, thus directly supporting the hypothesis that packing defects underlie instability in "live" or intact myelin. Our findings demonstrate that diffraction can provide a quantitative basis for understanding, at a molecular level, the membrane packing defects that occur in internodal myelin in demyelinating peripheral neuropathies.

Nodes of Ranvier are specialized axonal domains, at which voltage-gated sodium channels cluster. How axons cluster molecules in discrete domains is mostly unknown. Both axons and glia probably provide constraining mechanisms that contribute to domain formation. Proper sodium channel clustering in peripheral nerves depends on contact from Schwann cell microvilli, where at least one molecule, gliomedin, binds the sodium channel complex and induces its clustering. Furthermore, mice lacking Schwann cell dystroglycan have aberrant microvilli and poorly clustered sodium channels. Dystroglycan could interact at the basal lamina or at the axon-glial surface. Because dystroglycan is a laminin receptor, and laminin 2 mutations [merosin-deficient congenital muscular dystrophy (MDC1A)] cause reduced nerve conduction velocity, we asked whether laminins are involved. Here, we show that the composition of both laminins and the dystroglycan complex at nodes differs from that of internodes. Mice defective in laminin 2 have poorly formed microvilli and abnormal sodium clusters. These abnormalities are similar, albeit less severe, than those of mice lacking dystroglycan. However, mice lacking all Schwann cell laminins show severe nodal abnormalities, suggesting that other laminins compensate for the lack of laminin 2. Thus, although laminins are located at a distance from the axoglial junction, they are required for proper clustering of sodium channels. Laminins, through their specific nodal receptors and cytoskeletal linkages, may participate in the formation of mechanisms that constrain clusters at nodes. Finally, abnormal sodium channel clusters are present in a patient with MDC1A, providing a molecular basis for the reduced nerve conduction velocity in this disorder.