Transcription factor FoxO1 is essential for enamel biomineralization

• Published in: PloS one 2012-01, Vol.7 (1), p.e30357-e30357
• Main Authors: Poché, Ross A, Sharma, Ramaswamy, Garcia, Monica D, Wada, Aya M, Nolte, Mark J, Udan, Ryan S, Paik, Ji-Hye, DePinho, Ronald A, Bartlett, John D, Dickinson, Mary E
• Format: Article
• Language: English
• Subjects: Amelogenesis - genetics; Amelogenesis imperfecta; Animals; Biology; Biophysics; Bone morphogenetic proteins; Breast cancer; Calcification, Physiologic - genetics; Calcification, Physiologic - physiology; Cytokines; Dental enamel; Dental Enamel - growth & development; Dental Enamel - metabolism; Dentistry; Developmental biology; DNA binding proteins; Enamel; Extracellular matrix; Forkhead Box Protein O1; Forkhead protein; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - physiology; FOXO1 protein; Gene expression; Genes; Hardness Tests; Homeostasis; Hydroxyapatite; Integrases - genetics; Laboratories; Medicine; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mineralization; Morphogenesis; Mutation; Physiology; Proteins; Rodents; Signaling; Smad protein; Smad3 protein; Smad3 Protein - genetics; Smad3 Protein - metabolism; Smad3 Protein - physiology; Stem cells; Teeth; Tooth Calcification - genetics; Tooth diseases; Tooth Diseases - genetics; Tooth Diseases - pathology; Transcription activation; Transcription factors; Transcription Factors - genetics; Transcription Factors - physiology; Transforming growth factor-b; Transforming growth factors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0030357

The Transforming growth factor β (Tgf-β) pathway, by signaling via the activation of Smad transcription factors, induces the expression of many diverse downstream target genes thereby regulating a vast array of cellular events essential for proper development and homeostasis. In order for a specific cell type to properly interpret the Tgf-β signal and elicit a specific cellular response, cell-specific transcriptional co-factors often cooperate with the Smads to activate a discrete set of genes in the appropriate temporal and spatial manner. Here, via a conditional knockout approach, we show that mice mutant for Forkhead Box O transcription factor FoxO1 exhibit an enamel hypomaturation defect which phenocopies that of the Smad3 mutant mice. Furthermore, we determined that both the FoxO1 and Smad3 mutant teeth exhibit changes in the expression of similar cohort of genes encoding enamel matrix proteins required for proper enamel development. These data raise the possibility that FoxO1 and Smad3 act in concert to regulate a common repertoire of genes necessary for complete enamel maturation. This study is the first to define an essential role for the FoxO family of transcription factors in tooth development and provides a new molecular entry point which will allow researchers to delineate novel genetic pathways regulating the process of biomineralization which may also have significance for studies of human tooth diseases such as amelogenesis imperfecta.