title: Developmental and post-injury cortical gliogenesis: a genetic fate-mapping study with Nestin-CreER mice.
abstract: The primary sources of cortical gliogenesis, either during development or after adult brain injury, remain uncertain. We previously generated Nestin-CreER mice to fate-map the progeny of radial glial cells (RG), a source of astrocytes and oligodendrocytes in the nervous system. Here, we show that Nestin-CreER mice label another population of glial progenitors, namely the perinatal subventricular zone (SVZ) glioblasts, if they are crossed with stop-floxed EGFP mice and receive tamoxifen in late embryogenesis (E16-E18). Quantification showed E18 tamoxifen-induction labeled more perinatal SVZ glioblasts than RG and transitional RG combined in the newborn brain (54% vs. 22%). Time-lapse microscopy showed SVZ-glioblasts underwent complex metamorphosis and often-reciprocal transformation into transitional RG. Surprisingly, the E10-dosed RG progenitors produced astrocytes, but no oligodendrocytes, whereas E18-induction fate-mapped both astrocytes and NG2+ oligodendrocyte precursors in the postnatal brain. These results suggest that cortical oligodendrocytes mostly derive from perinatal SVZ glioblast progenitors. Further, by combining genetic fate-mapping and BrdU-labeling, we showed that cortical astrocytes cease proliferation soon after birth (<P10) and only undergo nonproliferative gliosis (i.e., increased GFAP expression without cell-division) after stab-wound injury in adult brains. By contrast, 9.7% of cortical NG2+ progenitors remained mitotic at P29, and the ratio rose to 13.8% after stab-wound injury. Together, these results suggest NG2+ progenitors, rather than GFAP+ astrocytes, are the primary source of proliferative gliosis after adult brain injury.
authors.affiliation: Division of Developmental Biology, Division of Neurology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Burns
authors.forename: Brian
authors.initials: B
authors.lastname: Murphy
authors.forename: Steve C
authors.initials: SC
authors.lastname: Danzer
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Kuan
mesh_terms: D000818:Animals; D000941:Antigens / Q000032:analysis / Q000378:metabolism; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D002540:Cerebral Cortex / Q000293:injuries / Q000378:metabolism / Q000503:physiopathology; D002874:Chromosome Mapping / Q000379:methods*; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis / Q000378:metabolism; D005911:Gliosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D049452:Green Fluorescent Proteins / Q000235:genetics; D007381:Intermediate Filament Proteins / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism*; D064231:Nestin; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D011509:Proteoglycans / Q000032:analysis / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D005904:Glial Fibrillary Acidic Protein; D049452:Green Fluorescent Proteins; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; D064231:Nestin; D011509:Proteoglycans; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D000099216:Chondroitin Sulfate Proteoglycan 4; C577485:Nes protein, mouse; C485184:enhanced green fluorescent protein