Moreover, FoxG1 removal in postmigratory cells did not result in the re-expression of the multipolar cell markers NeuroD1 and Unc5D (data not shown). These data strongly suggest that FoxG1 has a specialized function during the transition from the late multipolar cell phase into the cortical plate and does not play similar roles in the postmigratory populations. In summary, dynamic FoxG1 expression during the multipolar cell phase specifically coordinates pyramidal cell integration

into the cortical plate ( Figure 6A). This process appears to be mediated by two equivalently important steps: (1) a downregulation of FoxG1, allowing pyramidal neuron Alectinib clinical trial precursors to promptly transit through the multipolar phase by inducing Unc5D, and (2) subsequent upregulation of FoxG1 to leave the multipolar cell phase and enter into the cortical plate. In the present study, we have examined the role of FoxG1 in regulating the migration and maturation of postmitotic pyramidal neuron precursors ( Figure 6A). Specifically, we have observed that FoxG1 protein levels are dynamically regulated as pyramidal neurons migrate from the ventricular zone to the cortical plate. We demonstrate that the transient downregulation of FoxG1 at the beginning of the multipolar

phase enables cells to initiate Unc5D expression, which facilitates their transition from the early to late multipolar Epacadostat datasheet phase and is thus critical for their migration through the intermediate

zone. Failure to downregulate FoxG1 during this period delays the entrance into the cortical plate, resulting in a below superficial shift in both the laminar position and marker expression of pyramidal neurons. Subsequently, the upregulation of FoxG1 is specifically required for cells to transit out of the multipolar state and enter into the cortical plate. Taken together, we conclude that the dynamic regulation of FoxG1 is a crucial mechanism for controlling the incorporation of pyramidal neuron precursors into the cerebral cortex ( Figures 6A and 6B). These findings may have relevance to the etiology of specific classes of mental disorders observed in human patients, including congenital variants of Rett syndrome ( Ariani et al., 2008, Brunetti-Pierri et al., 2011 and Le Guen et al., 2011). Only relatively recently has it been recognized that pyramidal neuron precursors transiently adopt a characteristic multipolar morphology while they are migrating within the intermediate zone (Tabata and Nakajima, 2003 and Noctor et al., 2004; this study). However, the significance of this phase for the establishment of mature cortical networks remains unclear (LoTurco and Bai, 2006).