Abstract
Bone morphogenetic protein (BMP) signaling plays essential roles in the regulation of early tooth development. It is well acknowledged that extracellular BMP ligands bind to the type I and type II transmembrane serine/threonine kinase receptor complexes to trigger the BMP signaling pathway. Then, the receptor-activated Smad1/5/8 in cytoplasm binds to Smad4, the central mediator of the canonical BMP signaling pathway, to form transfer complexes for entering the nucleus and regulating target gene expression. However, a recent study revealed the functional operation of a novel BMP-mediated signaling pathway named the atypical BMP canonical signaling pathway in mouse developing tooth, which is Smad1/5/8 dependent but Smad4 independent. In this study, we investigated whether this atypical BMP canonical signaling is conserved in human odontogenesis. We showed that pSMAD1/5/8 is required for the expression of Msh homeobox 1 (MSX1), a well-defined BMP signaling target gene, in human dental mesenchyme, but the typical BMP canonical signaling is in fact not operating in the early human developing tooth, as evidenced by the absence of pSMAD1/5/8-SMAD4 complexes in the dental mesenchyme and translocation of pSMAD1/5/8, and the expression of MSX1 induced by BMP4 is mothers against decapentaplegic homolog 4 (SMAD4)-independent in human dental mesenchymal cells. Moreover, integrative analysis of RNA-Seq data sets comparing the transcriptome profiles of human dental mesenchymal cells with and without SMAD4 knockdown by siRNA displays unchanged expression profiles of pSMAD1/5/8 downstream target genes, further affirming the functional operation of the atypical canonical BMP signaling pathway in a SMAD1/5/8-dependent but SMAD4-independent manner in the dental mesenchyme during early odontogenesis in humans.
Highlights
The mouse tooth has long served as an excellent model system to study the molecular mechanism underlying mammalian odontogenesis
We provided compelling evidence that, as in the mouse, the atypical canonical Bone morphogenetic protein (BMP) signaling pathway is operating during early human tooth development
In the human dental mesenchyme, pSMAD1/5/8 are able to transduce BMP signal to regulate the expression of downstream target gene Msh homeobox 1 (MSX1) in a SMAD4 independent manner, as evidenced by the fact that MSX1 expression is inhibited by dorsomorphin in the human cap stage tooth germ and that knockdown of SMAD4 by siRNA exhibits no effect on BMP-induced pSMAD1/5/8 nuclear translocation and MSX1 expression in human dental mesenchymal cells (hDMCs)
Summary
The mouse tooth has long served as an excellent model system to study the molecular mechanism underlying mammalian odontogenesis. At the following bud stage, the expression of Bmp is shifted to the dental mesenchyme, which is activated by the mesenchymally expressed Msx and is being maintained there until the late differentiation stage. This mesenchymal Bmp, in turn, maintains Msx expression by forming a positive regulatory loop with Msx. Deletion of Msx revealed a dramatic downregulation of Bmp in dental mesenchyme and exhibited an arrest of tooth development at the bud stage. Mesenchymal BMP4 acts on the dental epithelium as a feedback signal to induce and maintain gene expression, such as Shh and p21, in the dental epithelium and is responsible for the formation of the enamel knot, a signaling center for tooth cusp patterning (Jernvall et al, 1998). BMP signaling is absolutely required for early tooth morphogenesis
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