, 2006). Second, Mek1,2\hGFAP conditional nulls that survive through the first postnatal week display a dorsal cortex that is almost completely devoid of astrocytes and exhibit a major neurodegeneration phenotype. Although both neurons and glia lack MEK in these mice, results from neuron-specific Mek-deleted mice suggest that neurons can survive into adulthood in the absence of MEK (data not shown), indicating the degeneration in Mek1,2\hGFAP dorsal cortices is probably due to the lack of glial support. A similar situation holds in the periphery where MEK/ERK signaling is required for Schwann cell development and neurons deprived of Schwann cell

support die massively during embryonic development ( Newbern et al., 2011). Finally, subcortical dopamine neuron survival GSK-3 assay has also been shown to be critically dependent on the astrocyte-derived trophic factors-conserved dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) ( Lindholm et al., 2007; Petrova et al., 2003). The nature of glial-derived survival signals for cortical neurons remains to be determined and should be a rich area for future investigation. It is important to note that postnatal regulation is critical to establishing the number this website of astrocytes and oligodendroglia in the

mature CNS. It has long been known that proliferation of OPCs postnatally is regulated by PDGF (Fruttiger et al., 1999). Very recently it has been demonstrated that mature-appearing astrocytes in upper cortical layers also proliferate in the postnatal period (Ge et al., 2012). Further recent studies demonstrate Levetiracetam that oligodendrocyte proliferation in spinal cord is partially under ERK/MAPK control (Newbern et al., 2011) and that constitutively active B-Raf can drive proliferation of spinal cord astrocyte precursors (Tien et al., 2012). These results, in combination with our results showing expansion of astrocytes in mice expressing caMek1, all strongly suggest that postnatal stages of glial development may also be regulated by MEK/ERK/MAPK signaling. Lastly, we note that astrocytes are now known to play critical roles in synapse

formation, elimination, and function (Allen and Barres, 2005; Christopherson et al., 2005; Stevens et al., 2007). However, the consequences of increasing astrocyte number for cortical neuronal physiology and behavior are unknown. Our MEK hyperactivation model may provide a unique approach to study the effects of changing the glia/neuron ratio on synapse formation and neuronal activity. Such studies may facilitate our understanding of the role of glia in the cognitive abnormalities observed in CFC syndrome patients. The Mek1f/f, Mek2−/−, Erk1-/, Erk2f/f, and CAG-loxpSTOPloxp-Mek1S218E,S222E (caMek1) mouse lines and associated genotyping procedures have been previously described ( Krenz et al., 2008; Newbern et al., 2008), and see Supplemental Experimental Procedures.