The central importance of FoxG1 as an essential transcriptional regulator is underscored by the observation that even subtle alterations in FoxG1 expression levels can have profound effects on brain development. Mice with heterozygous mutations in the FoxG1 gene have impaired pallial development, suggesting that the cortex is highly sensitive to FoxG1 gene dosage ( Eagleson

et al., 2007, Shen et al., 2006a and Siegenthaler et al., 2008). Similarly, in humans, cases of Rett syndrome have been attributed to haploinsufficiency of FoxG1 ( Ariani et al., 2008 and Le Guen et al., 2011). Moreover, duplication of the FoxG1 locus has been found in patients with epilepsy, mental retardation, and speech impairment ( Brunetti-Pierri et al., 2011). Alisertib These observations strongly suggest that the precise regulation of FoxG1 expression is critical for proper brain development. www.selleckchem.com/products/Bortezomib.html We hypothesized that the dynamic expression of FoxG1 in pyramidal neuron precursors is critical for proper cortical development, and to test this, we utilized both genetic gain- and loss-of-function approaches. Remarkably, we find that the observed dynamic variation in FoxG1 expression during pyramidal cell migration is crucial for the development of the cerebral cortex. Specifically, we find that a failure to downregulate FoxG1 at the

beginning of the multipolar phase transiently stalls pyramidal neuron precursors within the lower intermediate zone as a result of failure to express Unc5D. Cells perturbed in this fashion were ultimately displaced to more superficial layers, Oxygenase and their laminar identity was respecified accordingly. Whereas the downregulation of FoxG1 was essential for pyramidal cell migration, the reinitiation of FoxG1 expression following Unc5D expression was also critical for cells to leave the multipolar cell phase and to enter into the cortical plate. Taken together, our findings demonstrate that the dynamic expression of FoxG1 during the postmitotic multipolar cell phase critically regulates

the assembly and integration of pyramidal neuron precursors into the cortical network. In the developing cerebral cortex, we found that FoxG1 expression is transiently downregulated in nascent pyramidal neuron precursors located at the lower portion of the intermediate zone (E14.5 Figures 1A and 1B; see other embryonic stages for Figures S1A, S1B, and S1C, available online). By comparing the expression of FoxG1 to other transcription factors expressed within the ventricular (VZ) and intermediate (IZ) zones (Hevner et al., 2006), such as Neurogenin2 (Neurog2) ( Hand et al., 2005, Miyata et al., 2004 and Nguyen et al., 2006), Tbr2 ( Arnold et al., 2008 and Sessa et al., 2008) ( Figure 1C), and NeuroD1 ( Mattar et al., 2008) ( Figure 1D), we found that NeuroD1 expression, which is restricted to postmitotic cells ( Mattar et al., 2008), is complementary to FoxG1 ( Figures 1B and 1B′).