Sox2, which encodes an HMG box transcription factor, is known to regulate the differentiation of progenitor cells of the tongue into taste bud cells versus keratinocytes during development. To determine the neural dependence of Sox2 expression, glossopharyngeal nerves of mice were cut bilaterally. In unoperated mice, the expression of Sox2 mRNA and protein was restricted to a subset of taste bud cells and to the epithelium surrounding the taste buds of the circumvallate papillae. During the period of denervation, the taste buds largely disappeared; the taste bud cells and the epithelial cells with Sox2-immunoreactive (IR) nuclei decreased in number and totally disappeared from the epithelium by 16 days after denervation. When regenerated nerve fibers entered the epithelium, Sox2 expression reappeared, first in the epithelial cells, and then in the regenerating taste bud cells. In prenatal mice, Sox2 was expressed in the epithelium of the dorsal surface of circumvallate papillae, in regions into which numerous nerve fibers had entered. The results suggested that Sox2 expression was dependent on gustatory innervation. Sox2-IR cells in the taste buds were also examined by double-immunolabeling for 5-bromo-2'-deoxyuridine and cell-type markers such as cytokeratin 14, neural cell adhesion molecule, inositol 1,4,5-triphosphate receptor 3, and blood group H antigen. Sox2-IR cells were found in the populations of basal cells and of immature and some mature taste bud cells. A large number of Sox2-IR cells were identified as type-I cells, with a few being type-II and type-III cells.