Oncogenesis and altered differentiation induced by activated Ras in neuroblasts of transgenic mice

Abstract

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. Aberrations of these processes are responsible for a variety of developmental defects and malignancies. Many of the environmental signals influencing these precursor cells activate receptor tyrosine kinases that can signal, at least in part, via Ras pathways. To assess the extent to which Ras can alter neuroblast cell number and fate in vivo, we expressed activated H-Ras in transgenic mice using the dopamine-β-hydroxylase promoter, which directs expression to these cells prior to and after their differentiation. Ganglioneuromas and occasional neuroblastomas formed in the adrenal gland and preaortic sympathetic ganglia. Curiously, neurons of the superior cervical ganglia and the gut were largely unaffected despite demonstrated expression of activated Ras. The sensitivity of preaortic sympathetic neurons and adrenal chromaffin cells to the effects of oncogenes such as Ras may explain the predilection of neuroblastomas in humans to these sites. The ability to analyse neuroblastoma development in these mice may shed light on the molecular basis of certain types of human neuroblastoma.