Bmp4-Msx1 signaling and Osr2 control tooth organogenesis through antagonistic regulation of secreted Wnt antagonists

Jia, Shihai; Kwon, Hyukjae; Lan, Yu; Zhou, Jing; Liu, Han; Jiang, Rulang

doi:10.1016/j.ydbio.2016.10.001

Cited by 48 publications

(61 citation statements)

References 47 publications

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“…7 Combined with the decreased Msx1 transcription, the odontogenic capability of the Osr2-cre KI ; Ctnnb1 ex3f molar mesenchyme was supposed to be attenuated by the active Wnt/β-catenin signaling. 16 Correspondingly, the elevated Runx2 expression might represent the enhanced osteogenic tendency in Osr2-cre KI ; Ctnnb1 ex3f molar mesenchyme.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Wnt/β-catenin signaling induces Wnt and BMP antagonists in dental epithelium

Chen

Liu

et al. 2019

Organogenesis

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Previous studies indicated that the elevated mesenchymal Wnt/β-catenin signaling deprived dental mesenchyme of odontogenic fate. By utilizing ex vivo or pharmacological approaches, Wnt/β-catenin signaling in the developing dental mesenchyme was suggested to suppress the odontogenic fate by disrupting the balance between Axin2 and Runx2. In our study, the Osr2-cre KI ; Ctnnb1 ex3f mouse was used to explore how mesenchymal Wnt/β-catenin signaling suppressed the odontogenic fate in vivo. We found that all of the incisor and half of the molar germs of Osr2-cre KI ; Ctnnb1 ex3f mice started to regress at E14.5 and almost disappeared at birth. The expression of Fgf3 and Msx1 was dramatically down-regulated in the E14.5 Osr2-cre KI ; Ctnnb1 ex3f incisor and molar mesenchyme, while Runx2transcription was only diminished in incisor mesenchyme. Intriguingly, in the E14.5 Osr2-cre KI ; Ctnnb1 ex3f incisor epithelium, the expression of Noggin was activated, while Shh was abrogated. Similarly, the Wnt and BMP antagonists, Ectodin and Noggin were also ectopically activated in the E14.5 Osr2-cre KI ; Ctnnb1 ex3f molar epithelium. Recombination of E13.5 Osr2-cre KI ; Ctnnb1 ex3f molar mesenchyme with E10.5 and E13.5 WT dental epithelia failed to develop tooth. Taken together, the mesenchymal Wnt/β-catenin signaling resulted in the loss of odontogenic fate in vivo not only by directly suppressing odontogenic genes expression but also by inducing Wnt and BMP antagonists in dental epithelium.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal Wnt/β-catenin signaling induces Wnt and BMP antagonists in dental epithelium

Chen

Liu

et al. 2019

Organogenesis

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“…In the present study, we found NKX2-3 to be highly expressed in the enamel knot region of molars and involved in regulation of p21 expression in both primary and secondary enamel knots as a homeobox transcription factor. BMP2 and BMP4, as well as BMP7 are expressed in early dental epithelium and regulate tooth morphogenesis (42)(43)(44)(45)(46). The expression of Bmp4 shifts to the mesenchyme at the bud stage (47), indicating that BMPs are critical regulators for epithelial-mesenchymal interaction during early tooth development.…”

Section: Discussionmentioning

confidence: 99%

The transcription factor NKX2-3 mediates p21 expression and ectodysplasin-A signaling in the enamel knot for cusp formation in tooth development

Xue

Yoshizaki

Miyazaki

et al. 2018

Journal of Biological Chemistry

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Tooth morphogenesis is initiated by reciprocal interactions between the ectoderm and neural crest-derived mesenchyme. During tooth development, tooth cusps are regulated by precise control of proliferation of cell clusters, termed enamel knots, that are present among dental epithelial cells. The interaction of ectodysplasin-A (EDA) with its receptor, EDAR, plays a critical role in cusp formation by these enamel knots, and mutations of these genes is a cause of ectodermal dysplasia. It has also been reported that deficiency in , encoding a member of the NK2 homeobox family of transcription factors, leads to cusp absence in affected teeth. However, the molecular role of NKX2-3 in tooth morphogenesis is not clearly understood. Using gene microarray analysis in mouse embryos, we found that is highly expressed during tooth development and increased during the tooth morphogenesis, especially during cusp formation. We also demonstrate that NKX2-3 is a target molecule of EDA and critical for expression of the cell cycle regulator p21 in the enamel knot. Moreover, NKX2-3 activated the bone morphogenetic protein (BMP) signaling pathway by up-regulating expression levels of and in dental epithelium and decreased the expression of the dental epithelial stem cell marker SRY box 2 (SOX2). Together, our results indicate that EDA/NKX2-3 signaling is essential for enamel knot formation during tooth morphogenesis in mice.

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“…Pax9 also influences epithelial-mesenchymal signaling events that drive murine tooth morphogenesis (Peters et al, 1998;Nakatomi et al, 2010). Mutations in WNT10A account for the majority of human tooth agenesis cases (Bohring et al, 2009;van den Boogaard et al, 2012;Mues et al, 2014) and canonical Wnts are key drivers of tooth signaling interactions that are likely to be downstream of Pax9 in dental mesenchyme (O'Connell et al, 2012;Jia et al, 2016). Pax9 also integrates dental mesenchymal signaling events that involve Bmp4, Fgf3 or Fgf10 (Peters et al, 1998;Nakatomi et al, 2010).…”

Section: The Correction Of Pax9 Mutant Palatal Defects With Wnt Agonimentioning

confidence: 99%

Small-molecule Wnt agonists correct cleft palates in Pax9 mutant mice in utero

et al. 2017

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Clefts of the palate and/or lip are among the most common human craniofacial malformations and involve multiple genetic and environmental factors. Defects can only be corrected surgically and require complex life-long treatments. Our studies utilized the well-characterized mouse model with a consistent cleft palate phenotype to test small-molecule Wnt agonist therapies. We show that the absence of Pax9 alters the expression of Wnt pathway genes including and , proven antagonists of Wnt signaling. The functional interactions between Pax9 and Dkk1 are shown by the genetic rescue of secondary palate clefts in embryos. The controlled intravenous delivery of small-molecule Wnt agonists (Dkk inhibitors) into pregnant mice restored Wnt signaling and led to the growth and fusion of palatal shelves, as marked by an increase in cell proliferation and osteogenesis, while other organ defects were not corrected. This work underscores the importance of Pax9-dependent Wnt signaling in palatogenesis and suggests that this functional upstream molecular relationship can be exploited for the development of therapies for human cleft palates that arise from single-gene disorders.

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Bmp4-Msx1 signaling and Osr2 control tooth organogenesis through antagonistic regulation of secreted Wnt antagonists

Cited by 48 publications

References 47 publications

Mesenchymal Wnt/β-catenin signaling induces Wnt and BMP antagonists in dental epithelium

Mesenchymal Wnt/β-catenin signaling induces Wnt and BMP antagonists in dental epithelium

The transcription factor NKX2-3 mediates p21 expression and ectodysplasin-A signaling in the enamel knot for cusp formation in tooth development

Small-molecule Wnt agonists correct cleft palates in Pax9 mutant mice in utero

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