Changes in microtubule stability and density in myelin-deficient shiverer mouse CNS axons

Altered axon-Schwann cell interactions in PNS myelin-deficient Trembler mic e result in changed axonal transport rates, neurofilament and microtubule-a ssociated protein phosphorylation, neurofilament density, and microtubule s tability. To determine whether PNS and CNS myelination have equivalent effe cts on axons, neurofilaments, and microtubules in CNS, myelin-deficient shi verer axons were examined. The genetic defect in shiverer is a deletion in the myelin basic protein (MBP) gene, an essential component of CNS myelin. As a result, shiverer mice have little or no compact CNS myelin. Slow axona l transport rates in shiverer CNS axons were significantly increased, in co ntrast to the slowing in demyelinated PNS nerves. Even more striking were s ubstantial changes in the composition and properties of microtubules in shi verer CNS axons. The density of axonal microtubules is increased, reflectin g increased expression of tubulin in shiverer, and the stability of microtu bules is drastically reduced in shiverer axons. Shiverer transgenic mice wi th two copies of a wild-type myelin basic protein transgene have an interme diate level of compact myelin, making it possible to determine whether the actual level of compact myelin is an important regulator of axonal microtub ules. Both increased microtubule density and reduced microtubule stability were still observed in transgenic mouse nerves, indicating that signals bey ond synaptogenesis and the mere presence of compact myelin are required for normal regulation of the axonal microtubule cytoskeleton.