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Selective induction of neocortical GABAergic neurons by the PDK1-Akt pathway through activation of Mash1

Author:
Oishi, Koji, Watatani, Kenji, Itoh, Yasuhiro, Okano, Hideyuki, Guillemot, François, Nakajima, Kazunori, Gotoh, Yukiko
Source:
Proceedings of the National Academy of Sciences of the United States of America 2009 v.106 no.31 pp. 13064-13069
ISSN:
0027-8424
Subject:
brain, gene expression, neurons, signal transduction, somatomedins, transcriptional activation
Abstract:
Extracellular stimuli regulate neuronal differentiation and subtype specification during brain development, although the intracellular signaling pathways that mediate these processes remain largely unclear. We now show that the PDK1-Akt pathway regulates differentiation of telencephalic neural precursor cells (NPCs). Active Akt promotes differentiation of NPC into γ-aminobutyric acid-containing (GABAergic) but not glutamatergic neurons. Disruption of the Pdk1 gene or expression of dominant-negative forms of Akt suppresses insulin-like growth factor (IGF)-1 enhancement of NPC differentiation into neurons in vitro and production of neocortical GABAergic neurons in vivo. Furthermore, active Akt increased the protein levels and transactivation activity of Mash1, a proneural basic helix-loop-helix protein required for the generation of neocortical GABAergic neurons, and Mash1 was required for Akt-induced neuronal differentiation. These results have unveiled an unexpected role of the PDK1-Akt pathway: a key mediator of extracellular signals regulating the production of neocortical GABAergic neurons.
Agid:
2365558