Bcl11b/Ctip2 is required for development of lingual papillae in mice.

Molecular mechanisms underlying the development and morphogenesis of oral epithelia, comprising the gustatory and nongustatory epithelium, remain unclear. Here, we show that Bcl11b, a zinc finger transcription factor, plays an important role in the development of lingual papillae, especially filiform papillae. In both gustatory and nongustatory epithelium, Bcl11b was expressed in keratin 14-positive epithelial basal cells, which differentiate into keratinocytes and/or taste cells. Loss of Bcl11b function resulted in abnormal morphology of the gustatory papillae: flattened fungiform papillae, shorter trench wall in the foliate and circumvallate papillae, and ectopic invagination in more than half of circumvallate papillae. However, Bcl11b loss caused no effect on differentiation of taste receptor cells. In nongustatory epithelium, the impact of Bcl11b deficiency was much more striking, resulting in a smooth surface on the tongue tip and hypoplastic filiform papillae in the dorsal lingual epithelium. Immunohistochemical analyses revealed that a keratinocyte differentiation marker, Tchh expression was severely decreased in the Bcl11b(-/-) filiform papillae. In addition, expression of Pax9, required for morphogenesis of filiform papillae and its downstream target genes, hard keratins, almost disappeared in the tongue tip and was decreased in the dorsal tongue of Bcl11b(-/-) mice. Gene expression analyses demonstrated a delayed onset of expression of epithelial differentiation complex genes, which disturbed barrier formation in the mutant tongue. These results indicate that Bcl11b regulates the differentiation of keratinocytes in the tongue and identify Bcl11b as an essential factor for the lingual papilla morphogenesis.