Precursors with glial fibrillary acidic protein promoter activity transiently generate GABA interneurons in the postnatal cerebellum.
Neural stem or progenitor cells (NSC/NPCs) able to generate the different neuron and glial cell types of the cerebellum have been isolated in vitro, but their identity and location in the intact cerebellum are unclear. Here, we use inducible Cre recombination in GFAPCreER(T2) mice to irreversibly activate reporter gene expression at P2 (postnatal day 2), P5, and P12 in cells with GFAP (glial fibrillary acidic protein) promoter activity and analyze the fate of genetically tagged cells in vivo. We show that cells tagged at P2-P5 with beta-galactosidase or enhanced green fluorescent proteins reporter genes generate at least 30% of basket and stellate GABAergic interneurons in the molecular layer (ML) and that they lose their neurogenic potential by P12, after which they generate only glia. Tagged cells in the cerebellar white matter (WM) were initially GFAP/S100beta+ and expressed the NSC/NPCs proteins LeX, Musashi1, and Sox2 in vivo. One week after tagging, reporter+ cells in the WM upregulated the neuronal progenitor markers Mash1, Pax2, and Gad-67. These Pax2+ progenitors migrated throughout the cerebellar cortex, populating the ML and leaving the WM by P18. These data suggest that a pool of GFAP/S100beta+ glial cells located in the cerebellar WM generate a large fraction of cerebellar interneurons for the ML within the first postnatal 12 days of cerebellar development. This restricted critical period implies that powerful inhibitory factors may restrict their fate potential in vivo at later stages of development.
Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA.
John
J
Silbereis
Elise
E
Cheng
Yosif M
YM
Ganat
Laura R
LR
Ment
Flora M
FM
Vaccarino
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D019070:Cell Lineage / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D019426:Integrases / Q000378:metabolism; D007395:Interneurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011995:Recombination, Genetic / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D013629:Tamoxifen; D005680:gamma-Aminobutyric Acid; C045073:Cre recombinase; D019426:Integrases