Involvement of the Phosphatidylinositol 3-Kinase/Rac1 and Cdc42 Pathways in Radial Migration of Cortical Neurons

Abstract

During cortical development, newly generated neurons migrate radially toward their final positions. Although several candidate genes essential for this radial migration have been reported, the signaling pathways regulating it are largely unclear. Here we studied the role of phosphatidylinositol (PI) 3-kinase and its downstream signaling molecules in the radial migration of cortical neurons in vivo and in vitro. The expression of constitutively active and dominant-negative PI 3-kinases markedly inhibited radial migration. In the neocortical slice culture, a PI 3-kinase inhibitor suppressed the formation of GTP-bound Rac1 and Cdc42 and radial migration. Constitutively active and dominant-negative forms of Rac1 and Cdc42 but not Akt also significantly inhibited radial migration. In migrating neurons, wild-type Rac1 and Cdc42 showed different localizations; Rac1 localized to the plasma membrane and Cdc42 to the perinuclear region on the side of the leading processes. These results suggest that both the PI 3-kinase/Rac1 and Cdc42 pathways are involved in the radial migration of cortical neurons and that they have different roles. During cortical development, newly generated neurons migrate radially toward their final positions. Although several candidate genes essential for this radial migration have been reported, the signaling pathways regulating it are largely unclear. Here we studied the role of phosphatidylinositol (PI) 3-kinase and its downstream signaling molecules in the radial migration of cortical neurons in vivo and in vitro. The expression of constitutively active and dominant-negative PI 3-kinases markedly inhibited radial migration. In the neocortical slice culture, a PI 3-kinase inhibitor suppressed the formation of GTP-bound Rac1 and Cdc42 and radial migration. Constitutively active and dominant-negative forms of Rac1 and Cdc42 but not Akt also significantly inhibited radial migration. In migrating neurons, wild-type Rac1 and Cdc42 showed different localizations; Rac1 localized to the plasma membrane and Cdc42 to the perinuclear region on the side of the leading processes. These results suggest that both the PI 3-kinase/Rac1 and Cdc42 pathways are involved in the radial migration of cortical neurons and that they have different roles. During mammalian cortical development, neurons born in the cortical ventricular zone migrate radially, resulting in the inside-out formation of the cortical plate, which is composed of six layers. Although the molecular bases of radial migration are largely unknown, extracellular ligands and intracellular cytoskeletal and signaling components have been shown to be involved. Reelin, a large extracellular molecule secreted from Cajal-Retzius cells, is involved in the radial migration of cortical neurons and formation of the cortical plate (1Rice D.S. Curran T. Annu. Rev. Neurosci. 2001; 24: 1005-1039Crossref PubMed Scopus (579) Google Scholar). Recent studies (2Gleeson J.G. Walsh C.A. Trends Neurosci. 2000; 23: 352-359Abstract PubMed Scopus Google Rev. PubMed Scopus Google and have and molecules for migration in the and and their and in of cells, neurons, and their they in radial migration Trends PubMed Scopus Google Scholar). of have for and its in radial migration (2Gleeson J.G. Walsh C.A. Trends Neurosci. 2000; 23: 352-359Abstract PubMed Scopus Google Rev. PubMed Scopus Google Scholar). their to PubMed Scopus Google T. J.G. PubMed Scopus Google Scholar). In to Rac1 in a and the of a downstream of and in a resulting in the of PubMed Scopus Google (PI) phosphatidylinositol cortical ventricular phosphatidylinositol cortical ventricular which phosphatidylinositol is several extracellular a that is their and PubMed Scopus Google PubMed Scopus Google Scholar). downstream signaling molecules of PI 3-kinase have been In of cells, PI 3-kinase and migration Akt Rac1 and a are involved in the radial migration of cortical neurons T. PubMed Scopus Google Scholar). the of the PI 3-kinase/Rac1 Cdc42 pathways in migration not been we the of the PI 3-kinase/Rac1 and Cdc42 pathways in the radial migration of cortical neurons in vivo and in vitro. The and the of PI and but not Akt markedly inhibited radial migration. a PI 3-kinase inhibitor suppressed radial migration and the formation of GTP-bound Rac1 and Cdc42 in neocortical slice the of Rac1 and Cdc42 in migrating These results suggest different for the PI 3-kinase/Rac1 and Cdc42 pathways in the radial migration of cortical a mammalian expression PubMed Scopus Google Scholar). the expression the from expression for from T. from PubMed Scopus Google and and wild-type Rac1 and Cdc42 the from The and and the to in and and generated The and on Neurosci. PubMed Scopus Google Scholar). In expression and the of the and In and forms of the expression a of The expression and a of The and in and for the in and in from the of the The The for and for the in and and and These from and and a and from shown in of Rac1 and Cdc42 in migrating The of Rac1 and Cdc42 in migrating of wild-type Rac1 Cdc42 and the neocortical in and the to the of Rac1 and Cdc42 in migrating from and and the of the are shown in the and of the and the of cells, and the of the to the in the In and the and of the cortical plate the of the from 3-kinase of and Cdc42 in the the of on the of and for The of and and The from expression dominant-negative Akt and the neocortical in and of the region are shown Akt to the of and of The of and the of in of radial migration and dominant-negative Rac1 and expression constitutively active Rac1 Cdc42 dominant-negative Rac1 Cdc42 and the neocortical in and The of the region are shown the to the of and Rac1 Cdc42 of The of and the of in of of the PubMed Scopus Google In a expression in and from the of the of the on and in and a inhibitor of PI to the the of in the and and a and of the of on the radial migration of from the the of cells, the Rac1 and Cdc42 which is a of and the of T. 2001; PubMed Scopus Google Scholar). is to the of GTP-bound Rac1 and the of Rac1 and The expression a from The of the from and cortical These for in and The for that on the the of and and the of and the and of the from the role of PI 3-kinase and its downstream signaling molecules in the radial migration of cortical neurons, we in to expression signaling molecules the cortical of and we the radial migration of the neurons in the expression to both the and the region of the of the the region of the to on of the the and the of the and These migration not the of expression not for migration and not the migration. are in of of radial migration of cortical neurons the of the from in a the expression of the of PI 3-kinase cortical showed that the and cortical not the of PI 3-kinase cortical are of the of PI 3-kinases on the radial migration of cortical neurons constitutively active and dominant-negative forms of in vivo and for and the PI 3-kinases showed that and the PI 3-kinase in the and to the neurons PI a constitutively active of PI and the radial migration markedly of the in the and of the the which to the The expression of a dominant-negative of PI also suppressed the radial migration. The from the and the to the and neocortical slice culture, we the of a PI 3-kinase inhibitor on the radial migration. In of the the in and to the the toward the a PI 3-kinase inhibitor the radial migration of the and inhibited not the of and of the that they are of markedly in cells, in a in the inhibited migration but not the results suggest that PI 3-kinase is for the radial migration of cortical been that PI 3-kinase its downstream signaling which and showed the expression of and Cdc42 cortical not we their in the radial migration of cortical to the of on the and Cdc42 neocortical the of GTP-bound Rac1 and Cdc42 and Akt in a These results that and Cdc42 downstream of PI 3-kinase signaling cortical we the of Akt on the radial migration. dominant-negative and the radial migration of not of the and dominant-negative and on the radial migration not These results that a downstream of PI is not involved in the radial migration of cortical the of Rac1 and Cdc42 in the radial migration. constitutively active Rac1 and the radial migration of significantly to the in the PI The showed a of leading processes. The radial migration of dominant-negative Rac1 and also markedly and of the the and constitutively active Cdc42 and of the and of the in the and in the they dominant-negative Cdc42 and the radial migration this not that and These results suggest that Rac1 and Cdc42 are downstream molecules of PI 3-kinase different in the radial migration of cortical the different of Rac1 and Cdc42 in the radial we the of wild-type Rac1 and Cdc42 in radially migrating neurons in vivo The to the plasma membrane of migrating neurons localized to the perinuclear region on the side of the leading These results suggest that Rac1 and Cdc42 are involved in the radial migration of cortical neurons, in the of leading formation and neurons generated in the migrate and the the from the migration radial and in the (2Gleeson J.G. Walsh C.A. Trends Neurosci. 2000; 23: 352-359Abstract PubMed Scopus Google Rev. PubMed Scopus Google Scholar). PI and but not inhibited the radial migration of cortical The PI 3-kinase the a that the PI 3-kinase pathways to the radial migration but not to from the of PI been that signaling PI 3-kinase is involved in and 2001; PubMed Scopus Google Scholar). The of is to in the radial migration Neurosci. PubMed Google PubMed Scopus Google Scholar). is on the of radial PubMed Scopus Google and of their the of migrating neurons from radial Neurosci. PubMed Google PubMed Scopus Google Scholar). their radial of PI 3-kinase in the radial 3-kinase is to have a role in PI 3-kinase and its are involved in the of and PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google Scholar). In cells, is the of and the leading of the a PI a leading These suggest that the of the is for in that both and of PI 3-kinase markedly suppressed the radial migration of cortical neurons in cortical the PI 3-kinase inhibitor migration also suppressed the of migration inhibited migration not be to the that migrating neurons from radial the migrate results the suggest that the of PI 3-kinase in that to the in and be a role in the radial migration of cortical neurons it in the of that Rac1 and Cdc42 downstream signaling molecules of PI 3-kinase in migration. The PI 3-kinase/Rac1 Cdc42 pathways in the of and migration in mammalian PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google Scholar). The of PI the for the resulting in the of Cdc42 PubMed Scopus Google Scholar). In GTP-bound Rac1 and Cdc42 a of PI and PI 3-kinase PubMed Scopus Google PubMed Google which in the of pathways a the PI 3-kinase and Rac1 Cdc42 signaling pathways in the radial migration of cortical the of Rac1 and Cdc42 in migrating neurons 2000; PubMed Scopus Google the of the plasma membrane of Rac1 for in mammalian of to the plasma membrane is for the of its and cytoskeletal to the extracellular 2000; PubMed Scopus Google Scholar). we that neurons Rac1 their leading the membrane of Rac1 be for its and for the formation of leading their to radial The perinuclear of Cdc42 in migrating neurons to the the of its in the of migration. Cdc42 is also for 2001; PubMed Scopus Google and the of 2001; PubMed Scopus Google Scholar). In of the involved in a that is migration in the (2Gleeson J.G. Walsh C.A. Trends Neurosci. 2000; 23: 352-359Abstract PubMed Scopus Google Rev. PubMed Scopus Google Scholar). the perinuclear of Cdc42 the of Cdc42 for the of in migrating we a of PI and radial migration of cortical neurons Although we not the of downstream of PI 3-kinase in are studies on in and suggest in migration and the molecular migration and cortical for the PI 3-kinase/Rac1 and Cdc42 signaling pathways in migrating PI 3-kinase extracellular extracellular Rac1 and Cdc42 localized to the plasma membrane and region the the PI 3-kinase/Rac1 and Cdc42 pathways are involved in radial migration of cortical During mammalian cortical development, neurons born in the cortical ventricular zone migrate radially, resulting in the inside-out formation of the cortical plate, which is composed of six layers. Although the molecular bases of radial migration are largely unknown, extracellular ligands and intracellular cytoskeletal and signaling components have been shown to be involved. Reelin, a large extracellular molecule secreted from Cajal-Retzius cells, is involved in the radial migration of cortical neurons and formation of the cortical plate (1Rice D.S. Curran T. Annu. Rev. Neurosci. 2001; 24: 1005-1039Crossref PubMed Scopus (579) Google Scholar). Recent studies (2Gleeson J.G. Walsh C.A. Trends Neurosci. 2000; 23: 352-359Abstract PubMed Scopus Google Rev. PubMed Scopus Google and have and molecules for migration in the and and their and in of cells, neurons, and their they in radial migration Trends PubMed Scopus Google Scholar). of have for and its in radial migration (2Gleeson J.G. Walsh C.A. Trends Neurosci. 2000; 23: 352-359Abstract PubMed Scopus Google Rev. PubMed Scopus Google Scholar). their to PubMed Scopus Google T. J.G. PubMed Scopus Google Scholar). In to Rac1 in a and the of a downstream of and in a resulting in the of PubMed Scopus Google Scholar). (PI) phosphatidylinositol cortical ventricular phosphatidylinositol cortical ventricular which phosphatidylinositol is several extracellular a that is their and PubMed Scopus Google PubMed Scopus Google Scholar). downstream signaling molecules of PI 3-kinase have been In of cells, PI 3-kinase and migration Akt Rac1 and a are involved in the radial migration of cortical neurons T. PubMed Scopus Google Scholar). the of the PI 3-kinase/Rac1 Cdc42 pathways in migration not been Here we the of the PI 3-kinase/Rac1 and Cdc42 pathways in the radial migration of cortical neurons in vivo and in vitro. The and the of PI and but not Akt markedly inhibited radial migration. a PI 3-kinase inhibitor suppressed radial migration and the formation of GTP-bound Rac1 and Cdc42 in neocortical slice the of Rac1 and Cdc42 in migrating These results suggest different for the PI 3-kinase/Rac1 and Cdc42 pathways in the radial migration of cortical a mammalian expression PubMed Scopus Google Scholar). the expression the from expression for from T. from PubMed Scopus Google and and wild-type Rac1 and Cdc42 the from The and and the to in and and generated The and on Neurosci. PubMed Scopus Google Scholar). In expression and the of the and In and forms of the expression a of The expression and a of The and in and for the in and in from the of the The The for and for the in and and and These from and and a and from shown in of the and the of cells, and the of the to the in the In and the and of the cortical plate the of the from 3-kinase of and Cdc42 in the the of on the of and for The of and and The from expression dominant-negative Akt and the neocortical in and of the region are shown Akt to the of and of The of and the of in of radial migration and dominant-negative Rac1 and expression constitutively active Rac1 Cdc42 dominant-negative Rac1 Cdc42 and the neocortical in and The of the region are shown the to the of and Rac1 Cdc42 of The of and the of in of of the PubMed Scopus Google In a expression in and from the of the of the on and in and a inhibitor of PI to the the of in the and and a and of the of on the radial migration of from the the of cells, the Rac1 and Cdc42 which is a of and the of T. 2001; PubMed Scopus Google Scholar). is to the of GTP-bound Rac1 and the of Rac1 and The expression a from The of the from and cortical These for in and The for that on the the of and and the of and the and of the from a mammalian expression PubMed Scopus Google Scholar). the expression the from expression for from T. from PubMed Scopus Google and and wild-type Rac1 and Cdc42 the from The and and the to in and and generated The and In on Neurosci. PubMed Scopus Google Scholar). In expression and the of the and In and forms of the expression a of The expression and a of The and in and for the in and in from the of the The The for and for the in and and and These from and and a and from shown in of the and the of cells, and the of the to the in the In and the and of the cortical plate the of the from of of the PubMed Scopus Google In a expression in and from the of the of the on and in and a inhibitor of PI to the the of in the and and a and of the of on the radial migration of from the the of cells, the Rac1 and Cdc42 which is a of and the of T. 2001; PubMed Scopus Google Scholar). is to the of GTP-bound Rac1 and the of Rac1 and The expression a from The of the from and cortical These for in and The for that on the the of and and the of and the and of the from the role of PI 3-kinase and its downstream signaling molecules in the radial migration of cortical neurons, we in to expression signaling molecules the cortical of and we the radial migration of the neurons in the expression to both the and the region of the of the the region of the to on of the the and the of the and These migration not the of expression not for migration and not the migration. are in of of radial migration of cortical neurons the of the from in a the expression of the of PI 3-kinase cortical showed that the and cortical not the of PI 3-kinase cortical are of the of PI 3-kinases on the radial migration of cortical neurons constitutively active and dominant-negative forms of in vivo and for and the PI 3-kinases showed that and the PI 3-kinase in the and to the neurons PI a constitutively active of PI and the radial migration markedly of the in the and of the the which to the The expression of a dominant-negative of PI also suppressed the radial migration. The from the and the to the and neocortical slice culture, we the of a PI 3-kinase inhibitor on the radial migration. In of the the in and to the the toward the a PI 3-kinase inhibitor the radial migration of the and inhibited not the of and of the that they are of markedly in cells, in a in the inhibited migration but not the results suggest that PI 3-kinase is for the radial migration of cortical been that PI 3-kinase its downstream signaling which and showed the expression of and Cdc42 cortical not we their in the radial migration of cortical to the of on the and Cdc42 neocortical the of GTP-bound Rac1 and Cdc42 and Akt in a These results that and Cdc42 downstream of PI 3-kinase signaling cortical we the of Akt on the radial migration. dominant-negative and the radial migration of not of the and dominant-negative and on the radial migration not These results that a downstream of PI is not involved in the radial migration of cortical the of Rac1 and Cdc42 in the radial migration. constitutively active Rac1 and the radial migration of significantly to the in the PI The showed a of leading processes. The radial migration of dominant-negative Rac1 and also markedly and of the the and constitutively active Cdc42 and of the and of the in the and in the they dominant-negative Cdc42 and the radial migration this not that and These results suggest that Rac1 and Cdc42 are downstream molecules of PI 3-kinase different in the radial migration of cortical the different of Rac1 and Cdc42 in the radial we the of wild-type Rac1 and Cdc42 in radially migrating neurons in vivo The to the plasma membrane of migrating neurons localized to the perinuclear region on the side of the leading These results suggest that Rac1 and Cdc42 are involved in the radial migration of cortical neurons, in the of leading formation and the role of PI 3-kinase and its downstream signaling molecules in the radial migration of cortical neurons, we in to expression signaling molecules the cortical of and we the radial migration of the neurons in the expression to both the and the region of the of the the region of the to on of the the and the of the and These migration not the of expression not for migration and not the migration. are in the expression of the of PI 3-kinase cortical showed that the and cortical not the of PI 3-kinase cortical are of the of PI 3-kinases on the radial migration of cortical neurons constitutively active and dominant-negative forms of in vivo and for and the PI 3-kinases showed that and the PI 3-kinase in the and to the neurons PI a constitutively active of PI and the radial migration markedly of the in the and of the the which to the The expression of a dominant-negative of PI also suppressed the radial migration. The from the and the to the and neocortical slice culture, we the of a PI 3-kinase inhibitor on the radial migration. In of the the in and to the the toward the a PI 3-kinase inhibitor the radial migration of the and inhibited not the of and of the that they are of markedly in cells, in a in the inhibited migration but not the results suggest that PI 3-kinase is for the radial migration of cortical been that PI 3-kinase its downstream signaling which and showed the expression of and Cdc42 cortical not we their in the radial migration of cortical to the of on the and Cdc42 neocortical the of GTP-bound Rac1 and Cdc42 and Akt in a These results that and Cdc42 downstream of PI 3-kinase signaling cortical we the of Akt on the radial migration. dominant-negative and the radial migration of not of the and dominant-negative and on the radial migration not These results that a downstream of PI is not involved in the radial migration of cortical the of Rac1 and Cdc42 in the radial migration. constitutively active Rac1 and the radial migration of significantly to the in the PI The showed a of leading processes. The radial migration of dominant-negative Rac1 and also markedly and of the the and constitutively active Cdc42 and of the and of the in the and in the they dominant-negative Cdc42 and the radial migration this not that and These results suggest that Rac1 and Cdc42 are downstream molecules of PI 3-kinase different in the radial migration of cortical the different of Rac1 and Cdc42 in the radial we the of wild-type Rac1 and Cdc42 in radially migrating neurons in vivo The to the plasma membrane of migrating neurons localized to the perinuclear region on the side of the leading These results suggest that Rac1 and Cdc42 are involved in the radial migration of cortical neurons, in the of leading formation and neurons generated in the migrate and the the from the migration radial and in the (2Gleeson J.G. Walsh C.A. Trends Neurosci. 2000; 23: 352-359Abstract PubMed Scopus Google Rev. PubMed Scopus Google Scholar). PI and but not inhibited the radial migration of cortical The PI 3-kinase the a that the PI 3-kinase pathways to the radial migration but not to from the of PI been that signaling PI 3-kinase is involved in and 2001; PubMed Scopus Google Scholar). The of is to in the radial migration Neurosci. PubMed Google PubMed Scopus Google Scholar). is on the of radial PubMed Scopus Google and of their the of migrating neurons from radial Neurosci. PubMed Google PubMed Scopus Google Scholar). their radial of PI 3-kinase in the radial 3-kinase is to have a role in PI 3-kinase and its are involved in the of and PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google Scholar). In cells, is the of and the leading of the a PI a leading These suggest that the of the is for in that both and of PI 3-kinase markedly suppressed the radial migration of cortical neurons in cortical the PI 3-kinase inhibitor migration also suppressed the of migration inhibited migration not be to the that migrating neurons from radial the migrate results the suggest that the of PI 3-kinase in that to the in and be a role in the radial migration of cortical neurons it in the of that Rac1 and Cdc42 downstream signaling molecules of PI 3-kinase in migration. The PI 3-kinase/Rac1 Cdc42 pathways in the of and migration in mammalian PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google Scholar). The of PI the for the resulting in the of Cdc42 PubMed Scopus Google Scholar). In GTP-bound Rac1 and Cdc42 a of PI and PI 3-kinase PubMed Scopus Google PubMed Google which in the of pathways a the PI 3-kinase and Rac1 Cdc42 signaling pathways in the radial migration of cortical the of Rac1 and Cdc42 in migrating neurons 2000; PubMed Scopus Google the of the plasma membrane of Rac1 for in mammalian of to the plasma membrane is for the of its and cytoskeletal to the extracellular 2000; PubMed Scopus Google Scholar). we that neurons Rac1 their leading the membrane of Rac1 be for its and for the formation of leading their to radial The perinuclear of Cdc42 in migrating neurons to the the of its in the of migration. Cdc42 is also for 2001; PubMed Scopus Google and the of 2001; PubMed Scopus Google Scholar). In of the involved in a that is migration in the (2Gleeson J.G. Walsh C.A. Trends Neurosci. 2000; 23: 352-359Abstract PubMed Scopus Google Rev. PubMed Scopus Google Scholar). the perinuclear of Cdc42 the of Cdc42 for the of in migrating we a of PI and radial migration of cortical neurons Although we not the of downstream of PI 3-kinase in are studies on in and suggest in migration and the molecular migration and cortical neurons generated in the migrate and the the from the migration radial and in the (2Gleeson J.G. Walsh C.A. Trends Neurosci. 2000; 23: 352-359Abstract PubMed Scopus Google Rev. PubMed Scopus Google Scholar). PI and but not inhibited the radial migration of cortical The PI 3-kinase the a that the PI 3-kinase pathways to the radial migration but not to from the of PI been that signaling PI 3-kinase is involved in and 2001; PubMed Scopus Google Scholar). The of is to in the radial migration Neurosci. PubMed Google PubMed Scopus Google Scholar). is on the of radial PubMed Scopus Google and of their the of migrating neurons from radial Neurosci. PubMed Google PubMed Scopus Google Scholar). their radial of PI 3-kinase in the radial migration. PI 3-kinase is to have a role in PI 3-kinase and its are involved in the of and PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google Scholar). In cells, is the of and the leading of the a PI a leading These suggest that the of the is for in that both and of PI 3-kinase markedly suppressed the radial migration of cortical neurons in cortical the PI 3-kinase inhibitor migration also suppressed the of migration inhibited migration not be to the that migrating neurons from radial the migrate results the suggest that the of PI 3-kinase in that to the in and be a role in the radial migration of cortical neurons it in the of that Rac1 and Cdc42 downstream signaling molecules of PI 3-kinase in migration. The PI 3-kinase/Rac1 Cdc42 pathways in the of and migration in mammalian PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google Scholar). The of PI the for the resulting in the of Cdc42 PubMed Scopus Google Scholar). In GTP-bound Rac1 and Cdc42 a of PI and PI 3-kinase PubMed Scopus Google PubMed Google which in the of pathways a the PI 3-kinase and Rac1 Cdc42 signaling pathways in the radial migration of cortical the of Rac1 and Cdc42 in migrating neurons 2000; PubMed Scopus Google the of the plasma membrane of Rac1 for in mammalian of to the plasma membrane is for the of its and cytoskeletal to the extracellular 2000; PubMed Scopus Google Scholar). we that neurons Rac1 their leading the membrane of Rac1 be for its and for the formation of leading their to radial The perinuclear of Cdc42 in migrating neurons to the the of its in the of migration. Cdc42 is also for 2001; PubMed Scopus Google and the of 2001; PubMed Scopus Google Scholar). In of the involved in a that is migration in the (2Gleeson J.G. Walsh C.A. Trends Neurosci. 2000; 23: 352-359Abstract PubMed Scopus Google Rev. PubMed Scopus Google Scholar). the perinuclear of Cdc42 the of Cdc42 for the of in migrating we a of PI and radial migration of cortical neurons Although we not the of downstream of PI 3-kinase in are studies on in and suggest in migration and the molecular migration and cortical and for the of also and for the slice and