The regulatory region of the rat preproglucagon gene targets expression of the SV40 large T oncoprotein to two cell types in transgenic mice, the pancreatic α cells and a set of neurons localized in the hindbrain, both of which normally produce preproglucagon. Additional neurons in the forebrain and midbrain stain for T antigen but do not express the endogenous glucagon gene. Synthesis of T antigen in endocrine α cells results in the heritable development of pancreatic glucagonomas. In brains of transgenic mice from three independent lineages, expression of the hybrid gene begins at embryonic day 12 in neuroblasts of the hindbrain, where it continues throughout adult life, most notably in the medulla. Remarkably, oncoprotein expression in both proliferating neuroblasts and mature neurons has no apparent consequences, either phenotypic or tumorigenic. Expression of the hybrid glucagon gene in both neurons and islet cells supports a possible interrelationship between these cell types.