Platelet-derived growth factor receptor (PDGFRA)/NG2-expressing glia are distributed throughout the adult CNS. They are descended from oligodendrocyte precursors (OLPs) in the perinatal CNS, but it is not clear whether they continue to generate myelinating oligodendrocytes or other differentiated cells during normal adult life. We followed the fates of adult OLPs in Pdgfra-creER T2 /Rosa26-YFP double-transgenic mice and found that they generated many myelinating oligodendrocytes during adulthood; >20% of all oligodendrocytes in the adult mouse corpus callosum were generated after 7 weeks of age, raising questions about the function of the late-myelinating axons. OLPs also produced some myelinating cells in the cortex, but the majority of adult-born cortical cells did not appear to myelinate. We found no evidence for astrocyte production in gray or white matter. However, small numbers of projection neurons were generated in the forebrain, especially in the piriform cortex, which is the main target of the olfactory bulb.Oligodendrocytes, the myelin-forming cells of the CNS, are mostly generated during the first few postnatal weeks in rodents, peaking in the second week (postnatal day 7-14, P7-P14). They differentiate from proliferative, migratory OLPs that originate in the ventricular zones of the developing spinal cord and brain. OLPs express a characteristic set of markers, including PDGFRA and the NG2 proteoglycan, allowing OLP development to be followed in situ. Both PDGFRA and NG2 are rapidly downregulated when OLPs differentiate into oligodendrocytes 1-3 , unlike other lineage markers (for example, transcription factors SOX10 and OLIG2), which are expressed in both OLPs and oligodendrocytes. By the time of birth, OLPs are more or less evenly distributed throughout the brain, both in gray matter and developing white matter, and remain so during the early postnatal period, when oligodendrocyte production is in full swing. The size of the OLP population remains relatively stable throughout this time, presumably because, although OLPs continue to proliferate, half of the daughter cells either differentiate or die. To determine the behavior and fates of adult OLPs in vivo, we generated a transgenic mouse line that expresses a tamoxifen-inducible form of the Cre recombinase (CreER T2 ) under PDGFRA transcriptional control in a phage artificial chromosome (PAC). The PAC transgene was faithfully expressed by OLPs in the postnatal CNS. By combining PdgfracreER T2 mice with the Rosa26-YFP reporter line, we were able to induce expression of yellow fluorescent protein (YFP) de novo in adult OLPs and identify their differentiated progeny. We found that OLPs generated mature, myelinating oligodendrocytes in adult mice until at least 8 months of age, raising questions about the function of the newly myelinated axons. We were unable to find any evidence for astrocyte production from adult OLPs in either gray or white matter. Notably, we found small numbers of YFP-labeled neurons in the forebrain, particularly in th...

SummaryOligodendrocyte precursors (OPs) continue to proliferate and generate myelinating oligodendrocytes (OLs) well into adulthood. It is not known whether adult-born OLs ensheath previously unmyelinated axons or remodel existing myelin. We quantified OP division and OL production in different regions of the adult mouse CNS including the 4-month-old optic nerve, in which practically all axons are already myelinated. Even there, all OPs were dividing and generating new OLs and myelin at a rate higher than can be explained by first-time myelination of naked axons. We conclude that adult-born OLs in the optic nerve are engaged in myelin remodeling, either replacing OLs that die in service or intercalating among existing myelin sheaths. The latter would predict that average internode length should decrease with age. Consistent with that, we found that adult-born OLs elaborated much shorter but many more internodes than OLs generated during early postnatal life.

After central nervous system (CNS) demyelination-such as occurs during multiple sclerosis-there is often spontaneous regeneration of myelin sheaths, mainly by oligodendrocytes but also by Schwann cells. The origins of the remyelinating cells have not previously been established. We have used Cre-lox fate mapping in transgenic mice to show that PDGFRA/NG2-expressing glia, a distributed population of stem/progenitor cells in the adult CNS, produce the remyelinating oligodendrocytes and almost all of the Schwann cells in chemically induced demyelinated lesions. In contrast, the great majority of reactive astrocytes in the vicinity of the lesions are derived from preexisting FGFR3-expressing cells, likely to be astrocytes. These data resolve a long-running debate about the origins of the main players in CNS remyelination and reveal a surprising capacity of CNS precursors to generate Schwann cells, which normally develop from the embryonic neural crest and are restricted to the peripheral nervous system.

We determined the embryonic origins of adult forebrain subventricular zone (SVZ) stem cells by Cre-lox fate mapping in transgenic mice. We found that all parts of the telencephalic neuroepithelium, including the medial ganglionic eminence and lateral ganglionic eminence (LGE) and the cerebral cortex, contribute multipotent, self-renewing stem cells to the adult SVZ. Descendants of the embryonic LGE and cortex settle in ventral and dorsal aspects of the dorsolateral SVZ, respectively. Both populations contribute new (5-bromo-2Ј-deoxyuridine-labeled) tyrosine hydroxylase-and calretinin-positive interneurons to the adult olfactory bulb. However, calbindinpositive interneurons in the olfactory glomeruli were generated exclusively by LGE-derived stem cells. Thus, different SVZ stem cells have different embryonic origins, colonize different parts of the SVZ, and generate different neuronal progeny, suggesting that some aspects of embryonic patterning are preserved in the adult SVZ. This could have important implications for the design of endogenous stem cell-based therapies in the future.