Cellular distribution of the human neuroendocrine pancreatic polypeptide gene. The neuroendocrine pancreatic polypeptide (NPP) gene codes for a brain-gut peptide hormone that controls gastrointestinal motility. Previously, we have reported that NPP mRNA was specifically expressed in the islet and nerve cells of the islets of Langerhans (Bray and Ross, 1986, 1987). We now report on the cellular distribution of NPP mRNA in pancreas by in situ hybridization histochemistry using 35S-labeled anti-sense RNA probe. At the light microscopic level, NPP mRNA is localized in the cytoplasm of nerve cells of the islets and in the cytoplasm of glandular islet cells. NPP mRNA was also observed in nerve cells of islets and pancreas that appeared to be in preparation for regeneration following total pancreatectomy. High magnification of the islets demonstrated labeling of endocrine cells and nerve fibers. Double labeling studies using the fluorescent dye diaminofluorescein revealed that NPP mRNA was located in the nerve fibers that innervate the endocrine pancreas. The specificity of these data was demonstrated by our previous demonstration of the presence of NPP in normal rat pancreatic islet and gut. The specific cellular and islet organization of NPP mRNA distribution are similar to that reported for pancreatic polypeptide. Our findings are consistent with the concept that NPP functions as a neuromodulator or hormone with a role in gastrointestinal motility. NPP may also function as a neurotransmitter or modulator. The data are consistent with the concept that NPP functions as a neuromodulator or hormone with a role in gastrointestinal motility. NPP may also function as a neurotransmitter or modulator. The data are consistent with the concept that NPP functions as a neurotransmitter or modulator of the endocrine pancreas.