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 facto rs (IGFs). In the present study, in situ hybridization was used to exa mine the temporal and spatial expression of the IGF-I and IGF-II genes in rat sciatic nerve after crush. Such expression was characterized i n relation to Schwann cell proliferation and the presence of neurofila ments in returning axons during regeneration. The results show that bo th IGF-I and IGF-II mRNAs were increased in the sciatic nerve distal t o the crush site. However, each transcript had a distinctly different temporal and spatial distribution during regeneration. IGF-I gene expr ession was intensely increased at the crush site within 4 days after n erve crush. Along the portion of the nerve distal to the crush site, a moderate increase was observed to reach maximal levels 10 days postcr ush, and was decreased thereafter back towards baseline at 20 days pos tcrush. Furthermore, this increase was associated with the proliferati on of Schwann cells, and the return toward baseline with the regenerat ion of axons containing neurofilaments. By contrast, IGF-II gene expre ssion was unchanged at or near the site of injury, but unexpectedly wa s 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 di fferent roles during nerve regeneration. They support the hypotheses t hat IGF-I contributes to the initial sprouting and subsequent elongati on of axons in nerves, whereas IGF-II enhances the regeneration of cer tain axons into neuromuscular branches of nerves, and/or the re-establ ishment of neuromuscular synapses.