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Oncogenesis and altered differentiation induced by activated Ras in neuroblasts of transgenic mice
D A Sweetser1, R P Kapur, G J Froelick
1Department of Biochemistry, Howard Hughes Medical Institute, University of Washington, Seattle 98195, USA.
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-beta-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.
Insights
Activating the Ras pathway in neural crest cells of mice caused tumors, particularly neuroblastomas, in specific sympathetic ganglia and adrenal glands. This reveals Ras
Area of Science:
- Developmental biology
- Neuroscience
- Oncology
Background:
- Neural crest cells give rise to sympathetic neurons, enteric neurons, and adrenal chromaffin cells.
- Developmental processes like migration, proliferation, survival, and differentiation are crucial for neural crest derivatives.
- Aberrations in these processes can lead to developmental defects and cancers, including neuroblastomas.
Purpose of the Study:
- To investigate the in vivo role of Ras signaling in neuroblast cell number and fate.
- To determine if activated Ras can induce tumor formation in neural crest-derived cells.
Main Methods:
- Generation of transgenic mice expressing activated H-Ras using the dopamine-beta-hydroxylase promoter.
- Targeted expression of Ras to neural crest-derived cells before and after differentiation.
- Histological analysis of tumor formation in various neural crest derivatives.
Main Results:
- Expression of activated H-Ras led to ganglioneuromas and neuroblastomas in the adrenal gland and preaortic sympathetic ganglia.
- Neurons in the superior cervical ganglia and gut remained largely unaffected despite Ras expression.
- Demonstrated site-specific sensitivity of certain neural crest derivatives to Ras oncogenic signaling.
Conclusions:
- The Ras pathway plays a critical role in the development of specific neural crest-derived tumors.
- The predilection of human neuroblastomas to certain sites may be linked to the sensitivity of their precursor cells to oncogenes like Ras.
- These transgenic mice provide a valuable model for studying neuroblastoma development and its molecular basis.