title: RAS/ERK signaling controls proneural genetic programs in cortical development and gliomagenesis.
abstract: 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.
authors: Departments of Biochemistry and Molecular Biology, Departments of Pathology and Laboratory Medicine, Department of Medical Genetics, Hotchkiss Brain Institute, Alberta Children's Hospital Research Institute, and Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada, T2N 4N1, and Departments of Pediatrics and Medical Genetics, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7.
authors: Saiqun
authors: S
authors: Li
authors: Pierre
authors: P
authors: Mattar
authors: Rajiv
authors: R
authors: Dixit
authors: Samuel O
authors: SO
authors: Lawn
authors: Grey
authors: G
authors: Wilkinson
authors: Cassandra
authors: C
authors: Kinch
authors: David
authors: D
authors: Eisenstat
authors: Deborah M
authors: DM
authors: Kurrasch
authors: Jennifer A
authors: JA
authors: Chan
authors: Carol
authors: C
authors: Schuurmans
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D011905:Genes, ras / Q000502:physiology*; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D011247:Pregnancy
keywords: Neurog2 and Ascl1; RAS/ERK signaling; bHLH transcription factors; glioma and glioneuronal tumors; neurogenesis versus gliogenesis; proneural genetic switch