The timing of Shh/FGF8 treatment is of critical importance in determining their effects in early NPC: thus, it was shown that delayed application of these factors in NPC cultures obtained from human ES cells apparently induces differentiation of telencephalic DA neurons, as the resulting TH+ cells lack expression of midbrain-specific gene Engrailed1 (En1) and retain primitive bipolar morphology [70]. The gene discussed is EN1; the disease is nasopharyngeal carcinoma.