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Bmp4-Msx1 signaling and Osr2 control tooth organogenesis through antagonistic regulation of secreted Wnt antagonists
- Source :
- Developmental biology. 420(1)
- Publication Year :
- 2016
-
Abstract
- Mutations in MSX1 cause craniofacial developmental defects, including tooth agenesis, in humans and mice. Previous studies suggest that Msx1 activates Bmp4 expression in the developing tooth mesenchyme to drive early tooth organogenesis. Whereas Msx1-/- mice exhibit developmental arrest of all tooth germs at the bud stage, mice with neural crest-specific inactivation of Bmp4 (Bmp4ncko/ncko), which lack Bmp4 expression in the developing tooth mesenchyme, showed developmental arrest of only mandibular molars. We recently demonstrated that deletion of Osr2, which encodes a zinc finger transcription factor expressed in a lingual-to-buccal gradient in the developing tooth bud mesenchyme, rescued molar tooth morphogenesis in both Msx1-/- and Bmp4ncko/ncko mice. In this study, through RNA-seq analyses of the developing tooth mesenchyme in mutant and wildtype embryos, we found that Msx1 and Osr2 have opposite effects on expression of several secreted Wnt antagonists in the tooth bud mesenchyme. Remarkably, both Dkk2 and Sfrp2 exhibit Osr2-dependent preferential expression on the lingual side of the tooth bud mesenchyme and expression of both genes was up-regulated and expanded into the tooth bud mesenchyme in Msx1-/- and Bmp4ncko/ncko mutant embryos. We show that pharmacological activation of canonical Wnt signaling by either lithium chloride (LiCl) treatment or by inhibition of DKKs in utero was sufficient to rescue mandibular molar tooth morphogenesis in Bmp4ncko/ncko mice. Furthermore, whereas inhibition of DKKs or inactivation of Sfrp2 alone was insufficient to rescue tooth morphogenesis in Msx1-/- mice, pharmacological inhibition of DKKs in combination with genetic inactivation of Sfrp2 and Sfrp3 rescued maxillary molar morphogenesis in Msx1-/- mice. Together, these data reveal a novel mechanism that the Bmp4-Msx1 pathway and Osr2 control tooth organogenesis through antagonistic regulation of expression of secreted Wnt antagonists.
- Subjects :
- 0301 basic medicine
Molar
Mesenchyme
Organogenesis
Mutant
Morphogenesis
Bone Morphogenetic Protein 4
Mandible
Biology
Article
03 medical and health sciences
stomatognathic system
medicine
Animals
RNA, Messenger
Molecular Biology
Zinc finger transcription factor
Genetics
MSX1 Transcription Factor
Mice, Knockout
Wnt signaling pathway
Gene Expression Regulation, Developmental
Membrane Proteins
Tooth Germ
Cell Biology
Cell biology
Wnt Proteins
stomatognathic diseases
030104 developmental biology
medicine.anatomical_structure
Bone morphogenetic protein 4
Intercellular Signaling Peptides and Proteins
Lithium Chloride
Tooth
Developmental Biology
Signal Transduction
Transcription Factors
Subjects
Details
- ISSN :
- 1095564X
- Volume :
- 420
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Developmental biology
- Accession number :
- edsair.doi.dedup.....c6d008b2f3bf3aa9bbeed66feef3dd20