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Melatonin, a major pineal secretory product, exerts a range of physiological and neuroprotective effects. However, the functional significance of melatonin in determining neural identity, and the mechanisms by which this may occur, is unknown. In this study, P19 cells were used as a model system and cell behavior was monitored. Our data show that melatonin plays an important role in determining cell fate during neural commitment and promoting the differentiation of pluripotent P19 cells (Oct4+Sox2+) into neural stem cells (Oct4−Sox2+). This promotion appears to coincide with the activation of the MT1 receptor and phosphorylation of extracellular-signal-regulated kinases 1/2 (ERK1/2). Furthermore, our results show that melatonin regulates neural fate specification of P19 cells through two distinct mechanisms: the promotion of nuclear localization of ERK1/2 and upregulation of Sox2 transcription, and suppression of Smad1-induced expression of mesodermal-specific genes, such as Bra.