Defined regions (septum, substantia nigra) of the embryonic central nervous system (CNS) were transplanted into the sciatic nerves of young adult rats. Immunocytochemical techniques were used to examine the expression of neurotransmitter related enzymes and neuronal cytoskeletal proteins in the grafts.The origin of the septal grafts was confirmed by immunoreactivity in nenrons to choline acetyltransferase and the β-nerve growth factor receptor (192-IgG). In substantia nigra grafts, neuronal perikarya and processes were identified with an antibody directed against tyrosine hydroxylase. Typical spatial distributions of phosphorylated (Mr 200,000) and non phosphorylated (Mr 168,000 & 200,000) neurofilaments were observed in the short term (1-2 months) grafts with the monoclonal antibodies RT97 and SMI-32 respectively. Dense dendrite arbors and neuronal cell bodies were immunostained with an antibody that recognizes a high molecular weight microtubule associated protein (MAP2).In the long term (1 year) transplants, prominent cytoskeletal changes in the somata, axons and dendrites of neurons were evident. The cells showed a shift in phosphorylated neurofilament staining from the axon to the soma accompanied by a reduction in axonal immunoreactivity in the adjacent neuropil, Other abnormal features included swollen perikarya, hypertrophied axonal segments and Short segments of kinked axons. Regression of the dendrite trees in the long standing grafts was also apparent when sections were reacted with the MAP2 antibody.These experiments indicate that grafted fetal neurons, isolated in the peripheral nervous system, differentiate and express markers like their counterparts in situ. After extended time periods under these circumstances, cytoskeletal modifications become apparent in the neurons. These aberrant changes are similar to morphological characteristics associated with aging and neurodegenerative disorders. This experimental paradigm offers a new approach, to study cytoskeletal disturbances in neurons and provides a unique opportunity to examine conditions that may modulate the abnormal changes.