It is notable that Foxp4 can also repress Sox2, indicating that the suppression of N-cadherin may be achieved through both direct and indirect pathways.

Our results also demonstrate a similarity between the mechanism through which NPCs in the CNS detach from the neuroepithelium and the process of epithelial-mesenchymal transition carried out by neural crest progenitors. In both cases, the delamination of cells depends on both the downregulation of Sox2 activity and active repression of cadherin gene expression (Cano et al., 2000, Cimadamore et al., 2011 and Taneyhill et al., 2007). Whereas selleck kinase inhibitor neural crest cells are most dependent on the Slug/Snail family of transcriptional repressors (Cano et al., 2000 and Taneyhill et al., 2007), CNS progenitors rely on Foxp proteins. The capacity to repress cadherin expression and alter cellular junctions has been seen with many other Forkhead proteins including Foxc2, Foxd3, and Foxq1 (Amorosi et al., 2008, Cheung Onalespib et al., 2005, Dottori et al., 2001, Feuerborn et al., 2011 and Mani et al., 2007), suggesting that this is a conserved feature of this transcription factor family. Foxp2 is initially expressed throughout the neuroepithelium suggesting that its expression is most likely driven by broadly expressed progenitor factors. At these stages Foxp2 and Sox2 expression patterns are

largely overlapping, raising the possibility that they share the same upstream activators or that Foxp2 acts downstream of Sox2 to provide a negative feedback mechanism to limit the extent of N-cadherin expression. Foxp4, by contrast, is more dynamically expressed and primarily associated with cells that are beginning to differentiate. Foxp4 elevation coincides with the onset of Ngn2 and NeuroM expression in the ventral spinal cord and is turned off as these factors are extinguished PD184352 (CI-1040) in differentiated neurons, suggesting that proneural genes act upstream of Foxp4. This hierarchical relationship is confirmed by our findings that misexpression of the

Notch effector Hes5 can suppress Foxp4 in concert with proneural gene expression. Together, these data suggest that Foxp proteins act as downstream effectors of proneural genes and mediate some of their differentiation-promoting functions. This activity is further suggested by our epistasis test, which shows that proneural gene function is compromised and cells become trapped in a neuroepithelial state when Foxp2 and Foxp4 activities are knocked down. This latter result raises the possibility that loss of Foxp function could be a contributing factor toward the formation and growth of brain cancers, as many of these tumors display neuroepithelial characteristics and Foxp proteins have previously been implicated as tumor suppressors (Banham et al., 2001, Campbell et al., 2010 and Myatt and Lam, 2007).