A striking correlation between insulin-like growth factor II (IGF-II) gene expression and turnover of neuromuscular synapses was observed. The IGF-II gene was expressed at a high level in fetal rat hind limb muscles prior to the developmental formation of synapses and increased while polyneuronal innervation accumulated. Thereafter, there was a selective down-regulation of IGF-II mRNAs that was exactly coincident with the postnatal time course for elimination of superfluous synapses. The hypothesis that innervation might provide a signal suppressing IGF-II gene expression was tested. Upon transection of the sciatic nerve, there was up-regulation of IGF-II mRNA content in muscle. This up-regulation was selective and correlated with the capacity of denervated muscle to accept reinnervation. These results suggest that the IGF-II gene may play a role in the development and turnover of synapses.