, 2002 and Dawson et al., 2003; reviewed by Franklin and ffrench-Constant, 2008; Figure 1F). A small proportion of Tyrosine Kinase Inhibitor high throughput screening YFP+ cells were Aquaporin-4+

astrocytes (∼3%), but the great majority of reactive astrocytes were derived from Fgfr3-expressing cells (ependymal cells and/or preexisting astrocytes) ( Young et al., 2010), because they were YFP-labeled in Fgfr3-CreER∗: Rosa26-YFP mice ( Zawadzka et al., 2010). Schwann cells, the myelinating cells of the peripheral nervous system (PNS), are commonly found in remyelinating CNS lesions including some human multiple sclerosis lesions. Often these remyelinating Schwann cells surround blood vessels, which in the past has been taken to suggest that they enter the CNS from the PNS, using the vessels as a migration route. However Zawadzka et al. (2010) found that most remyelinating Schwann cells (Periaxin+) in their

CNS lesions were YFP+ in Pdgfra-CreER∗: Rosa26-YFP mice, suggesting that they were derived from NG2-glia ( Figure 1G). In strong support of this, the CNS-resident Schwann cells were also labeled in Olig2-Cre: Rosa26-YFP animals—Olig2 is not thought to be expressed outside of the CNS. Moreover, almost no CNS Schwann cells, but many Schwann cells in peripheral nerves, were labeled in Pzero-CreER∗: Rosa26-YFP mice. (Pzero is expressed in migrating neural crest and differentiated Schwann cells, but not in the oligodendrocyte lineage.) Schwann cells were not a minor side product of NG2-glia because 56% of all YFP+ cells in ethidium bromide-induced lesions were Periaxin+ Schwann cells. (Despite this, most new myelin is oligodendrocyte derived, because Schwann cells each remyelinate only a single internode,

INCB024360 purchase whereas oligodendrocytes remyelinate many.) To our knowledge, this is the clearest example to date of lineage plasticity among NG2-glia in vivo. Since both oligodendrocytes and Schwann cells are myelinating cells, relatively subtle reprogramming might be required to cross between them. In a different demyelinating model—experimental autoimmune encephalomyelitis (EAE), which causes more diffuse and widespread demyelination than gliotoxin injection—Tripathi et al. (2010) found robust production of NG2-glia-derived oligodendrocytes but very few Schwann cells. In EAE, there is a strong inflammatory component to the pathology that is not Rolziracetam present in gliotoxin-induced demyelination, suggesting that the local microenvironment in demyelinated lesions exerts a strong influence on the direction of differentiation of NG2-glia. Only a small fraction of YFP+ cells (1%–2%) were GFAP+ astrocytes in EAE, in keeping with the results from focal demyelination (Zawadzka et al., 2010). A relatively high proportion (∼10%) of YFP+ cells in this EAE study could not be identified, despite much effort with antibodies against microglia, macrophages, B or T cells, neutrophils, vascular endothelial cells, pericytes, neurons, astrocytes, oligodendrocytes, and Schwann cells.