Journal
STEM CELLS
Volume 30, Issue 11, Pages 2400-2411Publisher
WILEY
DOI: 10.1002/stem.1204
Keywords
Floor plate; FOXA2; Human embryonic stem cells; Sonic hedgehog; GLI
Categories
Funding
- University of Melbourne
- National Health and Medical Research Council of Australia [NHMRC:520165]
- Australian Research Council Initiative Stem Cells Australia
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The floor plate is one of the major organizers of the developing nervous system through its secretion of sonic hedgehog (Shh). Although the floor plate is located within the neural tube, the derivation of the floor plate during development is still debatable and some studies suggest that floor plate cells are specified by Shh in a temporarily restricted window different to neuroepithelial cells. Using human embryonic stem cells (hESC) as a model of neurogenesis, we sought to determine how floor plate cells may be temporarily specified by SHH signaling during human embryogenesis. We found that inhibition of both GSK3 beta and activin/nodal pathways in hESC induces a cellular state of SOX2+/PAX6- expression, we describe as pre-neuroepithelial. Exposure of SHH during this pre-neuroepithelial period causes the expression of GLI transcription factors to function as activators and consequently upregulate expression of the floor plate marker, FOXA2, while also supressing PAX6 expression to inhibit neuroepithelial fate. FOXA2+ cells were able to efficiently generate mesencephalic dopaminergic neurons, a floor plate derivative. Overall, this study demonstrates a highly efficient system for generating floor plate cells from hESC and, most importantly, reveals that specification of floor plate cells is temporally dependent, whereby it occurs prior to the onset of PAX6 expression, within a pre-neuroepithelial stage. STEM CELLS2012;30:24002411
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