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A cytoplasmic role of Wnt/β-catenin transcriptional cofactors Bcl9, Bcl9l, and Pygopus in tooth enamel formation

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Science Signaling  07 Feb 2017:
Vol. 10, Issue 465, eaah4598
DOI: 10.1126/scisignal.aah4598

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Cytoplasmic functions for transcriptional cofactors in teeth

Bcl9, Bcl9l, and Pygo2 interact with transcription factors, such as the Wnt-regulated protein β-catenin, to regulate gene expression. Cantù et al. reveal that these proteins also have cytoplasmic functions during tooth development and are particularly important for the formation of enamel. Mice lacking both Pygo1 and Pygo2 or both Bcl9 and Bcl9l developed teeth, a process that requires Wnt/β-catenin transcriptional regulation, but the enamel was structurally disorganized and contained less iron than teeth from control mice. Bcl9, Bcl9l, and Pygo2 were present in the cytoplasm of ameloblasts, the cells that secrete enamel proteins, and colocalized in these cells with amelogenin, the main component of enamel. Bcl9 interacted with amelogenin and proteins involved in exocytosis and vesicular trafficking, suggesting that these proteins function in the trafficking or secretion of enamel proteins. These results demonstrate that Bcl9, Bcl9l, and Pygo2 have cytoplasmic functions distinct from their roles as transcriptional cofactors downstream of Wnt signaling.


Wnt-stimulated β-catenin transcriptional regulation is necessary for the development of most organs, including teeth. Bcl9 and Bcl9l are tissue-specific transcriptional cofactors that cooperate with β-catenin. In the nucleus, Bcl9 and Bcl9l simultaneously bind β-catenin and the transcriptional activator Pygo2 to promote the transcription of a subset of Wnt target genes. We showed that Bcl9 and Bcl9l function in the cytoplasm during tooth enamel formation in a manner that is independent of Wnt-stimulated β-catenin–dependent transcription. Bcl9, Bcl9l, and Pygo2 localized mainly to the cytoplasm of the epithelial-derived ameloblasts, the cells responsible for enamel production. In ameloblasts, Bcl9 interacted with proteins involved in enamel formation and proteins involved in exocytosis and vesicular trafficking. Conditional deletion of both Bcl9 and Bcl9l or both Pygo1 and Pygo2 in mice produced teeth with defective enamel that was bright white and deficient in iron, which is reminiscent of human tooth enamel pathologies. Overall, our data revealed that these proteins, originally defined through their function as β-catenin transcriptional cofactors, function in odontogenesis through a previously uncharacterized cytoplasmic mechanism, revealing that they have roles beyond that of transcriptional cofactors.

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