A cytoplasmic role of Wnt/β-catenin transcriptional cofactors Bcl9, Bcl9l, and Pygopus in tooth enamel formation.
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.
Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
Claudio
C
Cantù
Orofacial Development and Regeneration, Institute of Oral Biology, Center of Dental Medicine, University of Zurich, 8032 Zurich, Switzerland.
Pierfrancesco
P
Pagella
Orofacial Development and Regeneration, Institute of Oral Biology, Center of Dental Medicine, University of Zurich, 8032 Zurich, Switzerland.
Tania D
TD
Shajiei
Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
Dario
D
Zimmerli
Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
Tomas
T
Valenta
Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
George
G
Hausmann
Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland. konrad.basler@imls.uzh.ch thimios.mitsiadis@zzm.uzh.ch.
Konrad
K
Basler
Orofacial Development and Regeneration, Institute of Oral Biology, Center of Dental Medicine, University of Zurich, 8032 Zurich, Switzerland. konrad.basler@imls.uzh.ch thimios.mitsiadis@zzm.uzh.ch.
Thimios A
TA
Mitsiadis
D048868:Adaptor Proteins, Signal Transducing; D000565:Ameloblasts / Q000378:metabolism; D000818:Animals; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D003743:Dental Enamel / Q000196:embryology / Q000378:metabolism* / Q000648:ultrastructure; D003746:Dental Enamel Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008855:Microscopy, Electron, Scanning; D009805:Odontogenesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C490890:Ambn protein, mouse; C545436:BCL9 protein, mouse; C568071:BCL9L protein, mouse; D003746:Dental Enamel Proteins; D047908:Intracellular Signaling Peptides and Proteins; C521908:Pygo1 protein, mouse; D014157:Transcription Factors; D051176:beta Catenin; C495570:pygopus 2 protein, mouse; C038456:tuftelin