Person: Bartlett, J.
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Bartlett
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Bartlett, J.
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Publication The Acid Test of Fluoride: How pH Modulates Toxicity(Public Library of Science, 2010) Sharma, Ramaswamy Narayanaswamy; Tsuchiya, Masahiro; Skobe, Ziedonis; Tannous, Bakhos; Bartlett, J.Background: It is not known why the ameloblasts responsible for dental enamel formation are uniquely sensitive to fluoride (\(F^−\)). Herein, we present a novel theory with supporting data to show that the low pH environment of maturating stage ameloblasts enhances their sensitivity to a given dose of \(F^−\). Enamel formation is initiated in a neutral pH environment (secretory stage); however, the pH can fall to below 6.0 as most of the mineral precipitates (maturation stage). Low pH can facilitate entry of \(F^−\) into cells. Here, we asked if \(F^−\) was more toxic at low pH, as measured by increased cell stress and decreased cell function. Methodology/Principal Findings: Treatment of ameloblast-derived LS8 cells with \(F^−\) at low pH reduced the threshold dose of \(F^−\) required to phosphorylate stress-related proteins, PERK, eIF2α, JNK and c-jun. To assess protein secretion, LS8 cells were stably transduced with a secreted reporter, Gaussia luciferase, and secretion was quantified as a function of \(F^−\) dose and pH. Luciferase secretion significantly decreased within 2 hr of \(F^−\) treatment at low pH versus neutral pH, indicating increased functional toxicity. Rats given 100 ppm \(F^−\) in their drinking water exhibited increased stress-mediated phosphorylation of eIF2α in maturation stage ameloblasts (pH<6.0) as compared to secretory stage ameloblasts (pH∼7.2). Intriguingly, \(F^−\)-treated rats demonstrated a striking decrease in transcripts expressed during the maturation stage of enamel development (Klk4 and Amtn). In contrast, the expression of secretory stage genes, AmelX, Ambn, Enam and Mmp20, was unaffected. Conclusions: The low pH environment of maturation stage ameloblasts facilitates the uptake of \(F^−\), causing increased cell stress that compromises ameloblast function, resulting in dental fluorosis.Publication Transcription Factor FoxO1 Is Essential for Enamel Biomineralization(Public Library of Science, 2012) Poché, Ross A.; Sharma, Ramaswamy; Garcia, Monica D.; Wada, Aya M.; Nolte, Mark J.; Udan, Ryan S.; Paik, Ji-Hye; DePinho, Ronald A.; Bartlett, J.; Dickinson, Mary E.The Transforming growth factor \(\beta\) (Tgf-\(\beta\)) 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-\(\beta\) 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.