Reconciliation of these findings will require additional work with careful attention to timing of recombination in neurogenic precursors. Interestingly, the phenotype of Mek-deleted brains was somewhat more severe than in Erk-deleted brains, an effect observed previously with other Cre lines ( Newbern et al., 2008; Newbern et al., 2011). Whether these differences relate to timing of the disappearance of protein www.selleckchem.com/products/BKM-120.html after Cre-mediated recombination has yet to be determined. Although ERK is

the only well-established downstream substrate of MEK ( Morandell et al., 2010), it is interesting that a few studies outside the nervous system have reported kinase activity-independent MEK functions that do not require ERK ( Scholl et al., GS-1101 research buy 2004; Wang et al., 2009). Whether MEK may function independently of ERK in the mammalian brain remains to be explored. We have found that the Ets family transcription factor Etv5/Erm is strongly regulated by MEK. Erm is a member of the PEA3 subgroup, which comprises Erm (Etv5), Er81 (Etv1), and Pea3 (Etv4). Ets transcription factors are well established as FGF targets and have been reported to be phosphorylated and transactivated

by the MAPK pathway (Bertrand et al., 2003; Chen et al., 2005; Sharrocks, 2001). Several prior studies have implicated Ets family members in regulation of gliogenesis. The Drosophila gene pointed, which encodes an Ets transcription factor, is critical for directing glial differentiation in the developing CNS of Drosophila ( Jacobs, 2000; Klaes et al., 1994). Indeed, a recent study has demonstrated an important role for a FGF-Rolled (Drosophila MAPK)-Pointed signaling cascade in inducing glia differentiation in the Drosophila eye ( Franzdóttir et al., 2009). In Xenopus, both loss- and gain-of-function studies demonstrated that RAS-MAPK signaling acts through Xenopus Ets-1 to regulate radial glia development ( Kiyota et al., 2007). In the mammalian

PNS, Erm has been implicated in glial cell fate decisions of neural crest progenitors ( Hagedorn et al., 2000). Although a previous study of Erm null mice found no gross abnormality in the brain, the glial population was not assessed ( Chen et al., 2005). As all three PEA3 subgroup members are expressed in progenitors and their sequences are highly homologous 3-mercaptopyruvate sulfurtransferase ( Hasegawa et al., 2004), loss of one family member may not have a drastic effect in vivo. However, our data clearly demonstrate that MEK specifically regulates Erm expression in radial progenitors, that Erm overexpression in radial progenitors is instructive in inducing glial progenitor specification and astrocyte differentiation, and that Erm introduction into Mek-deleted radial progenitors ex vivo can restore CNTF-induced astrogenesis. Additional mechanisms are likely to be at play. Another strongly regulated transcription factor is CoupTF-II (Table 1).