AXONAL REGULATION OF MYELIN PROTEIN SYNTHESIS

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Understanding the processes involved in the regulation of Schwann cell (SC) phenotype will greatly aid in the diagnosis and ultimate treatment of certain dysmyelinating peripheral neuropathies. It is well documented that neuronal axons influence many aspects of SC behavior, including the ability of SCs to achieve a mature, myelinating phenotype. It now appears that axonal contact can initiate the biosynthesis of the major myelin glycoprotein, PO, in the absence of active myelination, suggesting that the processes of myelin protein synthesis and myelin assembly are distinct events regulated independently. The studies presented in this proposal are aimed at obtaining an understanding of the mechanism whereby axons trigger SCs to synthesize myelin proteins in the absence or presence of active myelination. It is difficult to assay for the induction of myelin protein expression with SCs derived from myelinating nerve, as such cells continue to express PO (and perhaps other myelin proteins) in the absence of axonal influence. To alleviate this problem, SCs from the cervical sympathetic trunk (CST SCs) have been partially characterized and shown not to synthesize appreciable levels of PO either in vivo or after growth in culture. These cells will be characterized further and used to address the regulation of myelin protein synthesis. Experiments are proposed that will: 1) determine and compare the level of expression of the myelin proteins PO, MAG, and MBPs in non- myelinating and myelinating dorsal root ganglia (DRG)/endogenous SC cultures. This will reveal whether axons are sufficient to induce synthesis of other myelin proteins besides PO, as well as indicate the degree of upregulation of such proteins during active myelination; 2) quantitate the levels of PO, MAG, and MBPs biosynthesis in adult CST SCs to ascertain whether the expression of the latter two myelin proteins are suppressed to the same extent as PO; 3) determine the levels of synthesis of the myelin proteins by CST SCs after they have been seeded onto, DRG neurites in media that are capable and incapable of supporting myelination; 4) examine the DRG neurite cultures for the nature of the signal(s) triggering expression of myelin proteins. The CST SCs will be employed to aid in the assaying of such a component(s); 5) begin initial biochemical characterization and isolation of any myelin protein induction molecule(s) identified. The studies described should greatly increase the body of knowledge dealing with the expression of myelin proteins, and the culture systems employed will be useful in future studies addressing SC phenotypic changes.