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Background  Ameloblasts are epithelially derived cells responsible for enamel formation through a process known as amelogenesis. Amongst the several transcription factors that are expressed during amelogenesis, both  Msx2  and  Sp6  transcription factors play important role.  Msx2  and  Sp6  mouse mutants, exhibit similar amelogenesis defects, namely enamel hypoplasia, while humans with amelogenesis imperfecta (AI) carry mutations in the human homologues of MSX2 or SP6 genes. These across species similarities in function indicate that these two transcription factors may reside in the same developmental pathway. In this paper, we test whether they work in a coordinated manner to exert their effect during amelogenesis.    Methods  Two different dental epithelial cell lines, the mouse LS8 and the rat G5 were used for either overexpression or silencing of  Msx2  or  Sp6  or both.  Msx2  mutant mouse embryos or pups were used for  in vivo  studies.  In situ  hybridization, semi-quantitative and quantitative real time PCR were employed to study gene expression pattern.  MatInspector  was used to identify several potential putative  Msx2  binding sites upstream of the murine  Sp6  promoter region. Chromatin Immunoprecipitation (chIP) was used to confirm the binding of  Msx2  to  Sp6  promoter at the putative sites.    Results  Using the above methods we identified that (i)  Msx2  and  Sp6  exhibit overlapping expression in secretory ameloblasts, (ii)  Sp6  expression is reduced in the  Msx2  mouse mutant secretoty ameloblasts, and (iii) that  Msx2 , like  Sp6  inhibits  follistatin  expression. Specifically, our  loss-of  function studies by silencing  Msx2  and/or  Sp6  in mouse dental epithelial (LS8) cells showed significant downregulation of  Sp6  but upregulation of  Fst  expression. Transient transfection of  Msx2  overexpression plasmid, up-regulated  Sp6  and downregulated  Fst  expression. Additionally, using  MatInspector , we identified several potential putative  Msx2  binding sites, 3.5 kb upstream of the murine  Sp6  promoter region. By chIP, we confirmed the binding of  Msx2  to  Sp6  promoter at these sites, thus suggesting that  Sp6  is a direct target of  Msx2 .    Conclusion  Collectively, these results show that  Sp6  and  Msx2  work in a concerted manner to form part of a network of transcription factors that operate during later stages of tooth development controlling ameloblast life cycle and amelogenesis.

An Msx2-Sp6-Follistatin Pathway Operates During Late Stages of Tooth Development to Control Amelogenesis