期刊
JOURNAL OF NEUROSCIENCE
卷 34, 期 6, 页码 2169-2190出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4077-13.2014
关键词
bHLH transcription factors; glioma and glioneuronal tumors; Neurog2 and Ascl1; neurogenesis versus gliogenesis; proneural genetic switch; RAS/ERK signaling
资金
- Canadian Institutes of Health Research (CIHR) [MOP-44094]
- Kids Cancer Care Foundation
- Terry Fox Research Institute
- Alberta Cancer Foundation
- Alberta Innovates Health Solutions
- CIHR Training Grant in Genetics, Child Development, and Health
- Heart & Stroke Foundation Studentship
- AHFMR Studentship
- CIHR Canada Graduate Scholarship
- Killam Trust Award
- Lionel E. McLeod Health Research Scholarship
- Brain Tumour Foundation of Canada fellowship
Neural cell fate specification is well understood in the embryonic cerebral cortex, where the proneural genes Neurog2 and Ascl1 are key cell fate determinants. What is less well understood is how cellular diversity is generated in brain tumors. Gliomas and glioneuronal tumors, which are often localized in the cerebrum, are both characterized by a neoplastic glial component, but glioneuronal tumors also have an intermixed neuronal component. A core abnormality in both tumor groups is overactive RAS/ERK signaling, a pro-proliferative signal whose contributions to cell differentiation in oncogenesis are largely unexplored. We found that RAS/ERK activation levels differ in two distinct human tumors associated with constitutively active BRAF. Pilocytic astrocytomas, which contain abnormal glial cells, have higher ERK activation levels than gangliogliomas, which contain abnormal neuronal and glial cells. Using in vivo gain of function and loss of function in the mouse embryonic neocortex, we found that RAS/ERK signals control a proneural genetic switch, inhibiting Neurog2 expression while inducing Ascl1, a competing lineage determinant. Furthermore, we found that RAS/ERK levels control Ascl1's fate specification properties in murine cortical progenitors-at higher RAS/ERK levels, Ascl1(+) progenitors are biased toward proliferative glial programs, initiating astrocytomas, while at moderate RAS/ERK levels, Ascl1 promotes GABAergic neuronal and less glial differentiation, generating glioneuronal tumors. Mechanistically, Ascl1 is phosphorylated by ERK, and ERK phosphoacceptor sites are necessary for Ascl1's GABAergic neuronal and gliogenic potential. RAS/ERK signaling thus acts as a rheostat to influence neural cell fate selection in both normal cortical development and gliomagenesis, controlling Neurog2-Ascl1 expression and Ascl1 function.
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