It is generally believed that during mammalian embryogenesis neurons arise only from the ectodermal germ layer, while the other two germ layers, mesoderm and endoderm, give rise to connective tissue and gut, respectively. Pancreatic islet cells, however, may be an exception to this classical cell lineage derivation. These cells, of endodermal origin, can express several neuronal antigens in addition to the peptide hormones which regulate carbohydrate metabolism. This study sought to determine whether islet cells of adult mice, in addition to displaying biochemical homology to neurons, are also capable of extending neurites, the cytoplasmic elongations that are recognized as a hallmark of the neuronal phenotype. It was found that dissociated pancreatic islet cells can extend neurite-like processes when maintained in vitro and that these processes contain neurofilament, the intermediate filament protein specific to neurons. Islet cells maintained in vitro as explants, however, did not form neurites thereby indicating that normal histotypical contacts inhibit process formation. This observation may account for the absence of process elaboration by intact islets in vivo. These results demonstrate that cells derived from the endoderm share the ability to display a characteristic neuronal phenotype with neuroectodermal cells and, furthermore, that the expression of these traits is regulated by epigenetic cues.