DIFFERENTIAL SPATIOTEMPORAL EXPRESSION OF THE INSULIN-LIKE GROWTH-FACTOR GENES IN REGENERATING SCIATIC-NERVE

Previous studies have demonstrated that the regeneration of mammalian peripheral nerves is dependent on endogenous insulin-like growth factors (IGFs). In the present study, in situ hybridization was used to examine the temporal and spatial expression of the IGF-I and IGF-II genes in rat sciatic nerve after crush. Such expression was characterized in relation to Schwann cell proliferation and the presence of neurofilaments in returning axons during regeneration. The results show that both IGF-I and IGF-II mRNAs were increased in the sciatic nerve distal to the crush site. However, each transcript had a distinctly different temporal and spatial distribution during regeneration. IGF-I gene expression was intensely increased at the crush site within 4 days after nerve crush. Along the portion of the nerve distal to the crush site, a moderate increase was observed to reach maximal levels 10 days postcrush, and was decreased thereafter back towards baseline at 20 days postcrush. Furthermore, this increase was associated with the proliferation of Schwann cells, and the return toward baseline with the regeneration of axons containing neurofilaments. By contrast, IGF-II gene expression was unchanged at or near the site of injury, but unexpectedly was increased in more distal, intramuscular reaches of the nerves. This had a slower time course beginning 10 days postcrush, and was further increased at 20 days postcrush. These results show that the IGF-I and IGF-II genes are regulated by independent signals and probably play different roles during nerve regeneration. They support the hypotheses that IGF-I contributes to the initial sprouting and subsequent elongation of axons in nerves, whereas IGF-II enhances the regeneration of certain axons into neuromuscular branches of nerves, and/or the re-establishment of neuromuscular synapses.