Both insulin-like growth factor-I (IGF-I) and brain-derived neurotrophic factor (BDNF) induce the differentiation of post-mitotic neuronal precursors, derived from embryonic day 14 (E14) mouse striatal multipotent stem cells. Here we ask whether this differentiation is mediated by a member of the POU-III class of neural transcription factors. Exposure of stem cell progeny to either IGF-I or BDNF resulted in a rapid upregulation of Brn-4 mRNA and protein. Indirect immunocytochemistry with Brn-4 antiserum showed that the protein was expressed in newly generated neurons. Other POU-III genes, such as Brn-1 and Brn-2, did not exhibit this upregulation. Basic FGF, a mitogen for these neuronal precursors, did not stimulate Brn-4 expression. In the E14 mouse striatum, Brn-4-immunoreactive cells formed a boundary between the nestin-immunoreactive cells of the ventricular zone and the beta-tubulin-immunoreactive neurons migrating into the mantle zone. Loss of Brn-4 function during the differentiation of stem cell-derived or primary E14 striatal neuron precursors, by inclusion of antisense oligonucleotides, caused a reduction in the number of beta-tubulin-immunoreactive neurons. These findings suggest that Brn-4 mediates, at least in part, the actions of epigenetic signals that induce striatal neuron-precursor differentiation.