The developmental origin of oligodendrocyte progenitors (OLPs) in the forebrain has been controversial. We now show, by Cre-lox fate mapping in transgenic mice, that the first OLPs originate in the medial ganglionic eminence (MGE) and anterior entopeduncular area (AEP) in the ventral forebrain. From there, they populate the entire embryonic telencephalon including the cerebral cortex before being joined by a second wave of OLPs from the lateral and/or caudal ganglionic eminences (LGE and CGE). Finally, a third wave arises within the postnatal cortex. When any one population is destroyed at source by the targeted expression of diphtheria toxin, the remaining cells take over and the mice survive and behave normally, with a normal complement of oligodendrocytes and myelin. Thus, functionally redundant populations of OLPs compete for space in the developing brain. Notably, the embryonic MGE- and AEP-derived population is eliminated during postnatal life, raising questions about the nature and purpose of the competition.

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...

The neck and shoulder region of vertebrates has undergone a complex evolutionary history. To identify its underlying mechanisms we map the destinations of embryonic neural crest and mesodermal stem cells using Cre-recombinase-mediated transgenesis. The single-cell resolution of this genetic labelling reveals cryptic cell boundaries traversing the seemingly homogeneous skeleton of the neck and shoulders. Within this assembly of bones and muscles we discern a precise code of connectivity that mesenchymal stem cells of both neural crest and mesodermal origin obey as they form muscle scaffolds. The neural crest anchors the head onto the anterior lining of the shoulder girdle, while a Hox-gene-controlled mesoderm links trunk muscles to the posterior neck and shoulder skeleton. The skeleton that we identify as neural crest-derived is specifically affected in human Klippel-Feil syndrome, Sprengel's deformity and Arnold-Chiari I/II malformation, providing insights into their likely aetiology. We identify genes involved in the cellular modularity of the neck and shoulder skeleton and propose a new method for determining skeletal homologies that is based on muscle attachments. This has allowed us to trace the whereabouts of the cleithrum, the major shoulder bone of extinct land vertebrate ancestors, which seems to survive as the scapular spine in living mammals.