Selective induction of neocortical GABAergic neurons by the PDK1-Akt pathway through activation of Mash1 |
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| Authors: | Koji Oishi Kenji Watatani Yasuhiro Itoh Hideyuki Okano Fran?ois Guillemot Kazunori Nakajima Yukiko Gotoh |
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| Affiliation: | aInstitute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan; ;bDepartment of Anatomy and ;cDepartment of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan; and ;dDivision of Molecular Neurobiology, National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom |
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| 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. |
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| Keywords: | GABAergic neuronal differentiation neural precursor cells telencephalon |
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