TY - JOUR
T1 - MEK Is a Key Regulator of Gliogenesis in the Developing Brain
AU - Li, Xiaoyan
AU - Newbern, Jason M.
AU - Wu, Yaohong
AU - Morgan-Smith, Meghan
AU - Zhong, Jian
AU - Charron, Jean
AU - Snider, William D.
N1 - Funding Information:
We are grateful to G. Landreth (Case Western Reserve University) for providing us with Erk1 −/− and Erk2 fl/fl mutant mice, S. Arber (University of Basel, Switzerland) for Erm full-length cDNA; C. Der (UNC Lineberger Cancer Center) for the caMek1 construct; S. Gray and J. Samulski for the AAV9-EGFP virus; E. Anton, C. Birchmeier, and T. Muller (Max Delbrück Center for Molecular Medicine, Germany) for BLBP antibody; and E. Anton (UNC Neuroscience Center), Franck Polleux (Scripps Research Institute), and the members of the Snider lab for helpful discussions. This work was supported by NIH grant RO1 NS031768 to W.D.S.; K99NS076661 to J.M.N.; and the Confocal and Multiphoton Imaging Core, Functional Genomics Core, and Expression Localization Core Facilities funded by NINDS Center grant P30 NS045892.
PY - 2012/9/20
Y1 - 2012/9/20
N2 - We have defined functions of MEK in regulating gliogenesis in developing cerebral cortex using loss- and gain-of-function mouse genetics. Radial progenitors deficient in both Mek1 and Mek2 fail to transition to the gliogenic mode in late embryogenesis, and astrocyte and oligodendroglial precursors fail to appear. In exploring mechanisms, we found that the key cytokine-regulated gliogenic pathway is attenuated. Further, the Ets transcription family member Etv5/Erm is strongly regulated by MEK and Erm overexpression can rescue the gliogenic potential of Mek-deleted progenitors. Remarkably, Mek1/2-deleted mice surviving postnatally exhibit cortices almost devoid of astrocytes and oligodendroglia and exhibit neurodegeneration. Conversely, expression of constitutively active MEK1 leads to a major increase in numbers of astrocytes in the adult brain. We conclude that MEK is essential for acquisition of gliogenic competence by radial progenitors and that levels of MEK activity regulate gliogenesis in the developing cortex.
AB - We have defined functions of MEK in regulating gliogenesis in developing cerebral cortex using loss- and gain-of-function mouse genetics. Radial progenitors deficient in both Mek1 and Mek2 fail to transition to the gliogenic mode in late embryogenesis, and astrocyte and oligodendroglial precursors fail to appear. In exploring mechanisms, we found that the key cytokine-regulated gliogenic pathway is attenuated. Further, the Ets transcription family member Etv5/Erm is strongly regulated by MEK and Erm overexpression can rescue the gliogenic potential of Mek-deleted progenitors. Remarkably, Mek1/2-deleted mice surviving postnatally exhibit cortices almost devoid of astrocytes and oligodendroglia and exhibit neurodegeneration. Conversely, expression of constitutively active MEK1 leads to a major increase in numbers of astrocytes in the adult brain. We conclude that MEK is essential for acquisition of gliogenic competence by radial progenitors and that levels of MEK activity regulate gliogenesis in the developing cortex.
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U2 - 10.1016/j.neuron.2012.08.031
DO - 10.1016/j.neuron.2012.08.031
M3 - Article
C2 - 22998872
AN - SCOPUS:84866516735
SN - 0896-6273
VL - 75
SP - 1035
EP - 1050
JO - Neuron
JF - Neuron
IS - 6
ER -