Expression, gene regulation, and roles of Fisp12/CTGF in developing tooth germs

Tsuyoshi Shimo, Changshan Wu, Paul C. Billings, Ronald Piddington, Joel Rosenbloom, Maurizio Pacifici, Eiki Koyama

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)


Odontogenesis involves multiple events, including tissue-tissue interactions, cell proliferation, and cell differentiation, but the underlying mechanisms of regulation are far from clear. Because Fisp12/CTGF is a signaling protein involved in similar events in other systems, we asked whether it is expressed in developing tooth germs and what roles it may have. Indeed, Fisp12/CTGF transcripts were first expressed by dental laminas, invaginating epithelium, and condensing mesenchyme at the bud stage, and then became abundant in enamel knot and preameloblasts. Fisp12/CTGF was present not only in inner dental epithelium but also in stratum intermedium and underlying dental mesenchyme. Fisp12/CTGF expression decreased markedly in secreting ameloblasts. Tissue reconstitution experiments showed that Fisp12/CTGF expression in dental epithelium required interaction with mesenchyme but was maintained by treatment of epithelium with transforming growth factor-1, a factor regulating Fisp12/CTGF expression in other systems, or with bone morphogenetic protein-2. Loss-of-function studies using CTGF neutralizing antibodies revealed that interference with endogenous factor action in tooth germ explants led to a severe inhibition of proliferation in both epithelium and mesenchyme and a marked delay in cytodifferentiation of ameloblasts and odontoblasts. Treatment of dental epithelial and mesenchymal cells in culture with recombinant CTGF stimulated cell proliferation, whereas treatment with neutralizing antibodies inhibited it. The data demonstrate for the first time that Fisp12/CTGF is expressed during odontogenesis. Expression is confined to specific sites and times, is regulated by epithelial-mesenchymal interactions and critical soluble factors, and appears to be needed for proliferation and differentiation along both ameloblast and odontoblast cell lineages.

Original languageEnglish
Pages (from-to)267-278
Number of pages12
JournalDevelopmental Dynamics
Issue number3
Publication statusPublished - 2002
Externally publishedYes


  • Amelogenesis
  • Connective tissue growth factor
  • Epithelial-mesenchymal interactions
  • Fisp12
  • Tooth germ development

ASJC Scopus subject areas

  • Developmental Biology


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