TARGETED DISRUPTION OF THE NEURONAL NITRIC-OXIDE SYNTHASE GENE

By homologous recombination, we have generated mice that lack the neur onal nitric oxide synthase (NOS) gene. Neuronal NOS expression and NAD PH-diaphorase (NDP) staining are absent in the mutant mice. Very low l evel residual catalytic activity suggests that other enzymes in the br ain may generate nitric oxide. The neurons normally expressing NOS app ear intact, and the mutant NOS mice are viable, fertile, and without e vident histopathological abnormalities in the central nervous system. The most evident effect of disrupting the neuronal NOS gene is the dev elopment of grossly enlarged stomachs, with hypertrophy of the pyloric sphincter and the circular muscle layer. This phenotype resembles the human disorder infantile pyloric stenosis, in which gastric outlet ob struction is associated with the lack of NDP neurons in the pylorus.