TY - JOUR
T1 - Activated K-Ras, but Not H-Ras or N-Ras, regulates brain neural stem cell proliferation in a Raf/Rb-dependent manner
AU - Bender, R. Hugh F.
AU - Haigis, Kevin M.
AU - Gutmann, David H.
N1 - Publisher Copyright:
© 2015 AlphaMed Press.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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 some neurodevelopmental brain disorders (Costello syndrome and Noonan syndrome) are caused by germline activating 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-activated Ras molecule-expressing genetically engineered mouse strains, we demonstrate that activated K-Ras, but not H-Ras or N-Ras, expression increases brain NSC growth in a Raf-dependent, but Mek-independent, manner. Moreover, we show that activated K-Ras regulation of brain NSC proliferation requires Raf binding and suppression of retinoblastoma (Rb) function. Collectively, these observations establish tissue-specific differences in activated Ras molecule regulation of brain cell growth that operate through a noncanonical mechanism.
AB - 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 some neurodevelopmental brain disorders (Costello syndrome and Noonan syndrome) are caused by germline activating 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-activated Ras molecule-expressing genetically engineered mouse strains, we demonstrate that activated K-Ras, but not H-Ras or N-Ras, expression increases brain NSC growth in a Raf-dependent, but Mek-independent, manner. Moreover, we show that activated K-Ras regulation of brain NSC proliferation requires Raf binding and suppression of retinoblastoma (Rb) function. Collectively, these observations establish tissue-specific differences in activated Ras molecule regulation of brain cell growth that operate through a noncanonical mechanism.
KW - Cell proliferation
KW - Neural stem cells
KW - Raf kinases
KW - Ras proteins
KW - Retinoblastoma protein
UR - http://www.scopus.com/inward/record.url?scp=84929783046&partnerID=8YFLogxK
U2 - 10.1002/stem.1990
DO - 10.1002/stem.1990
M3 - Article
C2 - 25788415
AN - SCOPUS:84929783046
SN - 1066-5099
VL - 33
SP - 1998
EP - 2010
JO - STEM CELLS
JF - STEM CELLS
IS - 6
ER -