Neural stem cells (NSCs) give rise to all the major cell types in the brain, including neurons, oligodendrocytes, and astrocytes. However, the intracellular signaling pathways that govern brain NSC proliferation and differentiation have been incompletely characterized to date. Since several neurodevelopmental brain disorders (i.e., Costello syndrome, Noonan syndrome) are caused by germline mutations in the RAS genes, Ras small GTPases are likely critical regulators of brain NSC function. In the mammalian brain, Ras exists as three distinct molecules (H-Ras, K-Ras, and N-Ras), each with different subcellular localizations, downstream signaling effectors, and biological effects. Leveraging a novel series of conditional Ras molecule-expressing genetically-engineered mouse strains, we demonstrate that K-Ras, but not H-Ras or N-Ras, hyperactivation increases brain NSC growth in a Raf-dependent, but Mek-independent, manner. Moreover, we show that K-Ras regulation of brain NSC proliferation requires Raf binding and suppression of retinoblastoma (Rb) function. Collectively, these observations establish tissue-specific differences in Ras molecule regulation of brain cell growth that operate through a non-canonical mechanism
