Selective induction of neocortical GABAergic neurons by the PDK1-Akt pathway through activation of Mash1.
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 gamma-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.
Oishi
Koji
K
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Watatani
Kenji
K
Itoh
Yasuhiro
Y
Okano
Hideyuki
H
Guillemot
François
F
Nakajima
Kazunori
K
Gotoh
Yukiko
Y
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D019579:Neocortex / Q000166:cytology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D064413:3-Phosphoinositide-Dependent Protein Kinases; D051792:Basic Helix-Loop-Helix Proteins; D007334:Insulin-Like Growth Factor I; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005680:gamma-Aminobutyric Acid; C499317:Ascl1 protein, mouse; C578564:Pdpk1 protein, mouse