A Targeted NKX2.1 Human Embryonic Stem Cell Reporter Line Enables Identification of Human Basal Forebrain Derivatives

We have used homologous recombination in human embryonic stem cells (hESCs) to insert sequences encoding green fluorescent protein (GFP) into the NKX2.1 locus, a gene required for normal development of the basal forebrain. Generation of NKX2.1‐GFP+ cells was dependent on the concentration, timing, a...

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Published in:Stem cells (Dayton, Ohio) Ohio), 2011-03, Vol.29 (3), p.462-473
Main Authors: Goulburn, Adam L., Alden, Darym, Davis, Richard P., Micallef, Suzanne J., Ng, Elizabeth S., Yu, Qing C., Lim, Sue Mei, Soh, Chew‐Li, Elliott, David A., Hatzistavrou, Tanya, Bourke, Justin, Watmuff, Bradley, Lang, Richard J., Haynes, John M., Pouton, Colin W., Giudice, Antonietta, Trounson, Alan O., Anderson, Stewart A., Stanley, Edouard G., Elefanty, Andrew G.
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn
Cell Differentiation - genetics
Cell Differentiation - physiology
Cell Lineage - genetics
Cell Tracking - methods
Cells, Cultured
Embryonic Stem Cells - cytology
Embryonic Stem Cells - metabolism
FGF
Flow Cytometry - methods
Genes, Reporter
Human embryonic stem cells
Humans
Hypothalamus
MGE
Mice
Mice, Transgenic
Molecular Targeted Therapy - methods
Neurogenesis - genetics
Neurogenesis - physiology
NKX2.1
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Prosencephalon - cytology
Prosencephalon - embryology
Prosencephalon - physiology
Retinoic acid
Thyroid Nuclear Factor 1
Transcription Factors - genetics
Transcription Factors - metabolism
Ventral telencephalon
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Summary:We have used homologous recombination in human embryonic stem cells (hESCs) to insert sequences encoding green fluorescent protein (GFP) into the NKX2.1 locus, a gene required for normal development of the basal forebrain. Generation of NKX2.1‐GFP+ cells was dependent on the concentration, timing, and duration of retinoic acid treatment during differentiation. NKX2.1‐GFP+ progenitors expressed genes characteristic of the basal forebrain, including SHH, DLX1, LHX6, and OLIG2. Time course analysis revealed that NKX2.1‐GFP+ cells could upregulate FOXG1 expression, implying the existence of a novel pathway for the generation of telencephalic neural derivatives. Further maturation of NKX2.1‐GFP+ cells gave rise to γ‐aminobutyric acid‐, tyrosine hydroxylase‐, and somatostatin‐expressing neurons as well as to platelet‐derived growth factor receptor α‐positive oligodendrocyte precursors. These studies highlight the diversity of cell types that can be generated from human NKX2.1+ progenitors and demonstrate the utility of NKX2.1GFP/w hESCs for investigating human forebrain development and neuronal differentiation. STEM CELLS 2011;29:462–473
ISSN:1066-5099
1549-4918
DOI:10.1002/stem.587