Specificity Protein 7 Is Required for Proliferation and Differentiation of Ameloblasts and Odontoblasts

Abstract

The Sp7/Osterix transcription factor is essential for bone development. Mutations of the Sp7 gene in humans are associated with craniofacial anomalies and osteogenesis imperfecta. However, the role of Sp7 in embryonic tooth development remains unknown. Here we identified the functional requirement of Sp7 for dentin synthesis and tooth development. Sp7-null mice exhibit craniofacial dysmorphogenesis and are completely void of alveolar bone. Surprisingly, initial tooth morphogenesis progressed normally in Sp7-null mice. Thus the formation of alveolar bone is not a prerequisite for tooth morphogenesis. Sp7 is required for mineralization of palatal tissue but is not essential for palatal fusion. The reduced proliferative capacity of Sp7-deficient ectomesenchyme results in small and misshapen teeth with randomly arranged cuboidal preodontoblasts and preameloblasts. Sp7 promotes functional maturation and polarization of odontoblasts. Markers of mature odontoblast (Col1a, Oc, Dspp, Dmp1) and ameloblast (Enam, Amelx, Mmp20, Amtn, Klk4) are barely expressed in incisors and molar tissues of Sp7-null mice. Consequently, dentin and enamel matrix are absent in the Sp7-null littermates. Interestingly, the Sp7 expression is restricted to cells of the dental mesenchyme indicating the effect on oral epithelium-derived ameloblasts is cell-nonautonomous. Abundant expression of Fgf3 and Fgf8 ligand was noted in the developing tooth of wild-type mice. Both ligands were remarkably absent in the Sp7-null incisor and molar, suggesting cross-signaling between mesenchyme and epithelium is disrupted. Finally, promoter-reporter assays revealed that Sp7 directly controls the expression of Fgf-ligands. Together, our data demonstrate that Sp7 is obligatory for the differentiation of both ameloblasts and odontoblasts but not for the initial tooth morphogenesis. © 2018 American Society for Bone and Mineral Research.

Regulatory mechanisms of jaw bone and tooth development

“…In vitro culture of mouse ameloblast lineage cells (mALCs) revealed that Runx2 physically interacts with Fam50a to increase its binding affinity to the ameloblastin (Ambn) promoter (Kim et al, 2018). Tooth morphogenesis initially progresses normally in Osterix null mice; however, markers of mature ameloblasts (Enam, Amelx, Mmp20, Amtn, Klk4) have limited expression in incisors and molar tissues of these mice, and they lack enamel matrix (Bae et al, 2018).…”

Klf4 Promotes Dentinogenesis and Odontoblastic Differentiation via Modulation of TGF-β Signaling Pathway and Interaction With Histone Acetylation

“…At the cellular and molecular levels, growth factors and signaling pathways, such as TGF‐β/BMP, Fgf, and Hh signaling pathways, mediate extracellular “cross‐talk,” while TFs link different signaling pathways by responding to inductive signals and modulating the expression of other factors in a DNA sequence‐dependent manner. Odontoblasts in tooth development are usually regarded as a classic model to study terminal cell differentiation and are regulated by a certain set of TFs, such as Dlx3, Runx2 , and Sp7 , and signaling pathways in a temporal‐ and spatial‐specific manner; moreover, the related findings shed light on dental pulp regeneration. However, the detailed molecular mechanism underlying how TFs regulate odontoblast differentiation and modulate signaling pathways and odontoblast marker genes such as Dmp1 and Dspp remain unclear.…”

SP1 regulates KLF4 via SP1 binding motif governed by DNA methylation during odontoblastic differentiation of human dental pulp cells

“…Studies of the odontoblastic differentiation would contribute to a better understanding of tooth development as well as dental pulp regeneration. Such biological process has been extensively studied, and is regulated by several signaling pathways, such as TGF‐ß, WNT, and HH pathways and transcription factors including Sp7 , Dlx3 , Klf4 , etc . Global knockout of Sp7 in mice will lead to severe dentin hypoplasia and obviously abolish the expression of DMP1 and DSPP, which are the classical markers of odontoblasts, in incisors and molars .…”