ONCOGENESIS AND ALTERED DIFFERENTIATION-INDUCED BY ACTIVATED RAS IN NEUROBLASTS OF TRANSGENIC MICE

Sympathetic neurons, enteric neurons and adrenal chromaffin cells all derive from the neural crest. During development these cells migrate, proliferate, survive and differentiate in a highly controlled fashion influenced by local signals encountered during their migration. Aberra tions of these processes are responsible for a variety of developmenta l defects and malignancies, Many of the environmental signals influenc ing these precursor cells activate receptor tyrosine kinases that can signal, at least in part, via Ras pathways, To assess the extent to wh ich Ras can alter neuroblast cell number and fate in vivo, we expresse d activated H-Ras in transgenic mice using the dopamine-beta-hydroxyla se promoter, which directs expression to these cells prior to and afte r their differentiation. Ganglioneuromas and occasional neuroblastomas formed in the adrenal gland and preaortic sympathetic ganglia. Curiou sly, neurons of the superior cervical ganglia and the gut were largely unaffected despite demonstrated expression of activated Ras. The sens itivity of preaortic sympathetic neurons and adrenal chromaffin cells to the effects of oncogenes such as Ras may explain the predilection o f neuroblastomas in humans to these sites. The ability to analyse neur oblastoma development in these mice may shed light on the molecular ba sis of certain types of human neuroblastoma.