2007 Fiscal Year Final Research Report Summary
Regulation of neocortical neuronal migration by the PDKl-Akt pathway
| Project/Area Number |
18207014
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cell biology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
GOTOH Yukiko The University of Tokyo, Institute of Molecular and Cellular Biosciences, Professor (70252525)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Akt / PDK1 / cell motility / neocortical development |
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| Research Abstract |
In the mammalian neocortex, newly differentiated neurons migrate toward the brain surface where they form six-layered structure and establish elaborate neuronal network. Although we and other groups reported that the PDK1-Akt pathway plays a pivotal role in the regulation of cell motility in fibroblasts, it remained unknown whether this pathway also contributes to neuronal migration during brain development. No obvious phenotypes of neuronal migration have been reported in mice deficient in one or two Akt isoforms, likely due to functional compensation among the three Akt isoforms (Akt1-3). We have therefore generated mutant mice lacking PDK1 conditionally in the central nervous system by taking advantage of the Cre-LoxP system-We confirmed that Akt activity was greatly reduced in the neocortex of PDK1 mutant mice. Importantly, neocortical laminar structure was disorganized in these mice, as judged by the immunohistochemical distribution of laminar markers. Birth date analyses revealed that the migration of neocortical neurons was significantly delayed in the mutant mice. The delay of neuronal migration might be in part due to malformation of radial scaffolds required for neuronal migration toward the pial surface, since radial fibers of neuroepithelial cells were disorganized in the mutant mice. Furthermore, by the use of in utero gene transfer methods, we found that PDK1 gene deletion or expression of a dominant-negative form of Akt delayed neuronal migration in a cell-autonomous manner. These results suggest that the PDK1-Akt pathway plays important roles in promoting radial migration in the neocortex, possibly through both cell-autonomous and non-cell-autonomous mechanisms.
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Author(s)
Adachi, K, Mirzadeh, Z., Sakaguchi, M., Yamashita, T., Nikolcheva, T., Gotoh. Y., Peltz, G., Gong, L., Kawase, T., Alvarez-Buylla, A., Okano, H., Sawamoto, K.
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Journal Title
Stem Cells 25
Pages: 2827-2836
Description
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Author(s)
Hayakawa-Yano, Y., Nishida, K., Fukami, S., Gotoh. Y., Hirano, T., Nakagawa, T., Shimazaki, T., Okano, H.
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Journal Title
Stem Cells 25
Pages: 1410-1422
Description
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