Congenital colonic hypoganglionosis in murine trisomy 16--an animal model for Down's syndrome.

Human trisomy 21 (Down's syndrome) affects the development of multiple organ systems frequently including gastrointestinal anomalies such as Hirschsprung's disease. To elucidate the underlying morphogenetical mechanisms a murine model (trisomy 16 mouse) for Down's syndrome has been established. However, previous studies on trisomy 16 (TS 16) mice have been confined to non-enteric developmental disorders. Therefore, the aim of the present study was to assess the enteric nervous system and the morphology of the terminal colon in TS 16 mice during late intrauterine development. Immunohistochemical examination (protein gene product 9.5) revealed a reduction of myenteric ganglionic size and density as well as the presence of ectopic ganglia, thus resembling typical features of colonic hypoganglionosis and myenteric heterotopia. Enzyme histochemistry for NADPH-diaphorase showed a remarkable decrease of NADPH-positive neurons in TS 16 mice, whose sparse distribution was confined to a minor portion of the oligoneuronal myenteric ganglia. Electron microscopical studies of TS 16 mice confirmed the myenteric hypoganglionosis and, additionally, demonstrated the absence of submucosal neurons. Whereas neurons of controls were characterized by arborizing neuronal processes, neurons of TS 16 mice were reduced in size and exhibited only few and shortened cytoplasmic protrusions. Additionally, prominent bundles of parallel nerve fibers passed through the intermuscular zone and lacked the arborization pattern of normal neuropil. They were not observed in controls and resembled features of extrinsic nerves. Approximately one third of TS 16 mice developed a colonic dilatation proximally to an obstructed segment characterized by a pronounced hypoganglionosis. Although TS 16 mice did not develop complete aganglionosis, the abundance of nerve fiber bundles and the colonic dilatation were consistent with the morphological characteristics of Hirschsprung's disease. The findings suggest that even a hypoganglionosis characterized by ultrastructurally altered and NADPH-diaphorase-deficient neurons may be capable of provoking a functional intestinal obstruction. Similar abnormalities of the enteric nervous system as observed in TS 16 mice may also be present in such trisomy 21 patients who suffer from chronic intestinal motility disorders which are not caused by complete aganglionosis.