They next sought to take the SFEB-cultured precursors one step further down the forebrain pathway by treating them with Wnt3a – a signaling factor that blocks neural differentiation early in embryogenesis, but interestingly promotes the adoption of a pallial (dorsal) fate in cells already committed to the telencephalic lineage. Their experiments bore out the hypothesis that the same would occur under SFEB culture, with significant dose-dependent increases in the population of cells expressing pallial markers following late-stage treatment with Wnt3a. Further experiments in which the SFEB aggregates were treated with Sonic hedgehog (Shh) after between 4-10 days of culture sent the cells in the opposite direction, triggering an increase in number of basal telencephalic neurons arising from the precursors.
The ability to generate the cellular forebears of the telencephalon from mouse ES cells represents a landmark in stem cell biology research. From a purely developmental perspective, the close mirroring of in vivo gene expression patterns by the externally induced effects seen in SFEB culture experiments provides new food for thought for scientists studying the genetic regulation of neurogenesis, particularly in its implications for the neural default model, which states that ectodermal cells tend to assume a neural fate in the absence of molecular messages to the contrary. And the proof-of-principle demonstration of the amenability of ES cells to forebrain differentiation and regional specification provides new avenues for biomedical researchers and clinicians to explore in the struggle to find cures for a range of human neurological disorders, including Huntington’s and Alzheimer’s disease, that affect the mind’s highest functions.