, 2007; Ying et al., 2008). Further, an important recent report demonstrated that FGF10 determines the timing of the transition from neural epithelium to radial progenitor, a key event in neurogenesis (Sahara and O’Leary, 2009). Our study does not assess the role of MEK in mediating the FGF10 effect since recombination Perifosine in our study occurred after the neural epithelium stage. However, our finding that Mek deletion prevents an important step in radial progenitor fate transition in late embryogenesis clearly has parallels with the FGF10 result at an earlier stage in radial progenitor development. Importantly,

FGFs have previously been implicated in glial development ( Naruse et al., 2006; Seuntjens et al., Kinase Inhibitor Library 2009; Song and Ghosh, 2004). We suggest that FGF effects on regulating radial progenitor fate transitions are mediated via MEK/ERK signaling. Our findings provide strong evidence for an important interaction between MEK signaling and the CNTF/LIFRβ-gp130/JAK-STAT cascade, a major cytokine signaling pathway that promotes astrogenesis (Bonni et al., 1997). It has been well established that an increase in the gp130 expression level in radial progenitors at midembryogenesis is vital for initiating astrogenesis (He et al., 2005; Nakashima et al., 1999a). Importantly, we have demonstrated here that MEK was required

for the expression of gp130 by radial progenitors. Consequently, CNTF failed to induce STAT3 phosphorylation and GFAP expression efficiently in Mek1,2\Nes isothipendyl mutant progenitor cultures.

Our data suggest that MEK and CNTF/JAK-STAT pathways work contiguously in regulating astrogenesis. Thus, MEK signaling promotes gliogenic fate transition by radial progenitors, and then CNTF/JAK-STAT signaling induces further differentiation of astrocyte precursors. Progression along the oligodendrocyte lineage was also profoundly affected by Mek deletion. In line with our results, partial inhibition of ERK/MAPK signaling by deletion of Braf or Erk2 has previously been shown to inhibit CNS myelination, though the effect on radial progenitor fate transition to OPC was unclear ( Fyffe-Maricich et al., 2011; Galabova-Kovacs et al., 2008). Here, we have completely eliminated ERK/MAPK signaling by deleting Mek1/2 and show that the generation of OPCs in the developing cortex is almost completely blocked. MEK regulation of neurogenesis was not definitively addressed in this study due to uncertainty about the timing of recombination in relation to the major phases of neurogenesis which occur earlier than gliogenesis. A recent study showed a requirement for ERK2 in regulating the proliferation of neurogenic precursors at E14, although results were complex in that some layer markers showed depletion after Erk2 deletion but other layer markers showed expansion ( Pucilowska et al., 2012). Here, our data suggest prolonged neurogenesis at late embryonic stages in Mek-deleted cortices.