Transcription Factor FoxO1 Is Essential for Enamel Biomineralization

Poché, Ross A.; Sharma, Ramaswamy; Garcia, Monica D.; Wada, Aya; Nolte, Mark J.; Udan, Ryan S.; Paik, Ji Hye; DePinho, Ronald A.; Bartlett, John D.; Dickinson, Mary E.

doi:10.1371/journal.pone.0030357

Cited by 20 publications

(22 citation statements)

References 67 publications

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“…IIIA). In a previous study, the conditional knockout of FoxO1 in ameloblasts of the teeth was shown to result in a chalky, white tooth phenotype consistent with enamel hypomaturation and attrition 21 . FoxO1-res mice also demonstrated abnormally white, chalky incisors compared with wild-type littermates (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 89%

“…Here, we show that endothelial-specific deletion of FoxO1 essentially phenocopies the full knockout, the only obvious difference being in the formation of the branchial arches. By contrast, embryonic development is not compromised in mice with lineage-specific deletions of FoxO1 in bone 18 , liver 19 , heart 7 , T cells 20 , and teeth enamel 21 . Collectively, these findings suggest that embryonic lethality in the full knockout is attributed primarily to the loss of FoxO1 in the endothelium.…”

Section: Discussionmentioning

confidence: 99%

“…Conditional deletion of all three FoxO factors in the endothelium is compatible with survival and protects against atherosclerosis in low-density lipoprotein receptor knockout mice 17 . Mice with lineage-specific knockouts of FoxO1 in other tissues, including bone 18 , liver 19 , heart 7 , T cells 20 , and teeth enamel 21 , are viable, but have wide-ranging phenotypes, implying an important role for this transcription factor in homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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FOXO1-Mediated Activation of Akt Plays a Critical Role in Vascular Homeostasis

Dharaneeswaran

Abid

Yuan

et al. 2014

Circulation Research

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Rationale Forkhead box-O transcription factors (FoxOs) transduce a wide range of extracellular signals, resulting in changes in cell survival, cell cycle progression, and a number of cell type-specific responses. FoxO1 is expressed in many cell types, including endothelial cells. Previous studies have shown that FoxO1 knockout in mice results in embryonic lethality at E11 due to impaired vascular development. In contrast, somatic deletion of FoxO1 is associated with hyperproliferation of endothelial cells. Thus, the precise role of FoxO1 in the endothelium remains enigmatic. Objective To determine the effect of endothelial-specific knockout and overexpression of FoxO1 on vascular homeostasis. Methods and Results We show that endothelial cell (EC)-specific disruption of FoxO1 in mice phenocopies the full knockout. While endothelial expression of FoxO1 rescued otherwise FoxO-null animals, overexpression of constitutively active FoxO1 resulted in increased EC size, occlusion of capillaries, elevated peripheral resistance, heart failure and death. Knockdown of FoxO1 in ECs resulted in marked inhibition of basal and VEGF-induced Akt-mTOR1 signaling. Conclusions Our findings suggest that in mice endothelial expression of FoxO1 is both necessary and sufficient for embryonic development. Moreover, FoxO1-mediated feedback activation of Akt maintains growth factor-responsive Akt/mTORC1 activity within a homeostatic range.

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Section: Resultsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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FOXO1-Mediated Activation of Akt Plays a Critical Role in Vascular Homeostasis

Dharaneeswaran

Abid

Yuan

et al. 2014

Circulation Research

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“…Previous studies have also shown that ameloblast morphology remains unaltered in Smad3 2/2 mice although the enamel is poorly mineralized due to defective protein removal at the maturation stage (Yokozeki et al, 2003). Recently, it was reported that Smad3 and FoxO1 (transcriptional co-factor for Smads) collaboratively regulate genes involved in enamel formation (Poché et al, 2012). Interestingly, in both Smad3 and FoxO1 mutant teeth, the expression of Ambn, Amelx, Enam, Mmp20 and Klk4 were all significantly downregulated.…”

Section: -Fold) In the Enamel Organs Of Itgb6mentioning

confidence: 96%

Critical role for αvβ6 integrin in enamel biomineralization

Mohazab

Koivisto

Jiang

et al. 2012

Journal of Cell Science

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SummaryTooth enamel has the highest degree of biomineralization of all vertebrate hard tissues. During the secretory stage of enamel formation, ameloblasts deposit an extracellular matrix that is in direct contact with the ameloblast plasma membrane. Although it is known that integrins mediate cell-matrix adhesion and regulate cell signaling in most cell types, the receptors that regulate ameloblast adhesion and matrix production are not well characterized. We hypothesized that avb6 integrin is expressed in ameloblasts where it regulates biomineralization of enamel. Human and mouse ameloblasts were found to express both b6 integrin mRNA and protein. The maxillary incisors of Itgb6 2/2 mice lacked yellow pigment and their mandibular incisors appeared chalky and rounded. Molars of Itgb6 2/2 mice showed signs of reduced mineralization and severe attrition. The mineral-to-protein ratio in the incisors was significantly reduced in Itgb6 2/2 enamel, mimicking hypomineralized amelogenesis imperfecta. Interestingly, amelogenin-rich extracellular matrix abnormally accumulated between the ameloblast layer of Itgb6 2/2 mouse incisors and the forming enamel surface, and also between ameloblasts. This accumulation was related to increased synthesis of amelogenin, rather than to reduced removal of the matrix proteins. This was confirmed in cultured ameloblast-like cells, in which avb6 integrin was not an endocytosis receptor for amelogenins, although it participated in cell adhesion on this matrix indirectly via endogenously produced matrix proteins. In summary, integrin avb6 is expressed by ameloblasts and it plays a crucial role in regulating amelogenin deposition and/or turnover and subsequent enamel biomineralization.

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“…miR-1271, which was more highly expressed in hDFC, was shown to be one of the miRNAs that target FOXO1. A previous study showed that the FOXO family of transcription factors has an essential role in tooth development and in regulation of the process of biomineralization (23). Based on these results, the miRNAs that are highly expressed in each cell type target and regulate the expression specific mRNAs.…”

Section: Discussionmentioning

confidence: 93%

Comparative Analysis of MicroRNA-mRNA Expression Profiles of Mesenchymal Stem Cells and Dental Follicle Cells

Ogura

Takahashi²,

Iwai³

et al. 2012

Int J Oral-Med Sci

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Small non-coding microRNAs (miRNAs) regulate cellular and developmental processes through the modulation of target gene expression and/or protein synthesis. miRNAs are expressed in a cell-specific manner. Human mesenchymal bone marrow stem cells (hMSC) and human dental follicle cells (hDFC) can undergo multilineage differentiation into various connective tissue cell types, and may therefore be utilized for regeneration in cell therapy. To elucidate the molecular differences that underlie the more primitive characteristics of hMSC and hDFC, we performed a comprehensive comparative analysis of the miRNA and mRNA expression profiles of hMSC and hDFC using a two-fold change in the normalized intensity of expression as a cut-off to determine differences in expression. In hMSC, 37 were more highly expressed, while 32 miRNAs more highly expressed in hDFC.hMSC expressed high levels of miR-196a, -196b, and miR-10a, -10b, which target several homeobox (HOX) genes associated with the patterning of the vertebrate axial skeleton.hMSC, but not hDFC, expressed high mRNA levels of HOX genes. In contrast, miR-199b, which is expressed in tooth germ, as well as the forkhead box O1 (FOXO1) gene, a target of miR-1271, were more highly expressed in DFC than in hMSC. The FOXO1 transcription factor plays a role in tooth development and regulates biomineralization. These miRNAs showed specific expression in tissues from which stem cells originate, suggesting that they influence the characteristic mRNA expression of these tissues. These data suggest that analysis of miRNA-mRNA expression profiles is useful for characterization of specific tissue types and cell-specific markers.

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Transcription Factor FoxO1 Is Essential for Enamel Biomineralization

Cited by 20 publications

References 67 publications

FOXO1-Mediated Activation of Akt Plays a Critical Role in Vascular Homeostasis

FOXO1-Mediated Activation of Akt Plays a Critical Role in Vascular Homeostasis

Critical role for αvβ6 integrin in enamel biomineralization

Comparative Analysis of MicroRNA-mRNA Expression Profiles of Mesenchymal Stem Cells and Dental Follicle Cells

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