The rat neurofibromatosis type I (NF1) gene expresses several transcript isoforms which differ by the alternative splicing of exons 23a and 23b in the region encoding the GTPase-activating protein-related domain. The significance of this alternative splicing event is unclear and the factors which influence isoform expression are largely unknown. Here we show that a variety of factors can modulate the expression of these isoforms in PC12 cells. Nerve growth factor and dexamethasone lead to an increase in the type I isoform concurrent with a decrease in cellular proliferation. Upregulation of the type I isoform by dexamethasone occurs in an RNA synthesis-dependent manner. Cycloheximide treatment leads to the detection of an additional species identified as the murine type III transcript. These results suggest that the NF1 alternative splicing event can respond to environmental cues. The changes in the type of NF1 transcript expressed may be important in the normal physiological regulation of neurofibromin and may modulate its role in differentiation and proliferation.