We further found that MBP staining was strikingly enhanced throughout all cortical Small molecule library solubility dmso layers in caMek1\hGFAP mice ( Figures S7A–S7B′), indicating changes in oligodendrocyte production ( Fruttiger et al., 1999), MBP levels ( Ishii et al., 2012),

or both. The increase in GFAP-labeled cells was particularly remarkable. GFAP+ astrocytes are normally restricted to white matter in mature WT mice. In caMek1\hGFAP dorsal cortices, GFAP+ cells filled the entire cortex occupying both gray and white matter ( Figures 8C and 8C′). Further, we noted a major increase in the number of Ki67+ astrocytes in postnatal day 10 cortices in the caMek1\hGFAP mice ( Figures S7D and S7E). Thus, the increased astrocyte number observed in mature mice is probably due to both an increase in the number of radial progenitors that committed to the astrocytic lineage and further proliferation of astrocyte precursors/astrocytes postnatally. We have demonstrated that MEK signaling strongly regulates the generation of glia from radial progenitors in developing cortex. This conclusion is based on multiple clear-cut in vivo findings in genetically induced loss- and gain-of-function models. First,

glial-like properties of radial progenitors are not maintained in Mek-deleted mice and glial specification is almost completely blocked. Second, expression of Cre or caMek1 in individual radial progenitors suggests that functions of MEK are cell autonomous and can be Org 27569 instructive. Third, Mek deletion leads to a persistent loss of gliogenic selleck kinase inhibitor competence as Mek1,2\hGFAP mutants are nearly devoid of astrocytes and oligodendrocytes in the dorsal cortex at postnatal stages. Finally, expression of caMek1 in radial progenitors leads to a major increase in numbers of cortical astrocytes in mature mice. Our data establish MEK as a key regulator of gliogenesis in developing mammalian cortex. In developing cortex, radial progenitors first generate neurons to form neuronal circuits and then generate matching numbers of glial cells (Guillemot

and Zimmer, 2011). Multiple studies have demonstrated that extrinsic factors such as Notch and BMP stimulate progenitors to become gliogenic (Gaiano and Fishell, 2002; Nakashima et al., 1999b; Rowitch and Kriegstein, 2010). Interestingly, many of these gliogenic cues are present at early neurogenic stages but do not induce gliogenesis (Molné et al., 2000; Takizawa et al., 2001). An idea that has emerged is that radial progenitors undergo a cell fate switch at the gliogenic stage making them competent to respond to gliogenic signals (Molné et al., 2000; Song and Ghosh, 2004; Viti et al., 2003). We suggest that MEK/ERK MAPK signaling mediates this switch from neurogenic to gliogenic competence. ERK MAPK signaling has been implicated previously in cell fate switching.