Generation of transgenic mice expressing insulin-like growth factor-1 under the control of the myelin basic protein promoter: increased myelination and potential for studies on the effects of increased IGF-1 on experimentally and genetically induced demyelination.

In order to investigate a role for insulin-like growth factor-1 (IGF-1) in ameliorating the effects of demyelinating events and potentiating remyelination, we have generated transgenic (tg) mice expressing IGF-1 under the control of the myelin basic protein promoter. Heterozygous tg mice expressed the highest levels of IGF-1 in brain during the most active periods of myelination as determined by Western and Northern blotting. A high level of expression was found throughout the lives of the tg mice. There was no increased expression of IGF-1 in other organs. The brains of heterozygous mice were larger than those of normal mice by 2 weeks of age, and they continued to increase in size for several months. Light and electron microscopy showed extensive myelination of axons. Behavioral studies of the older heterozygous mice documented difficulty with balance. This new tg mouse model can be bred to mice that are heterozygous for genetic leukodystrophies to produce eventually mice that are affected with a given leukodystrophy but overexpress IGF-1 during myelination and remyelination. It will be interesting to see if overexpression of IGF-1 can modulate the pathological and clinical features of the inherited leukodystrophies with or without supplemental therapies.