EVIDENCE FOR THE ROLE OF THE ENAMEL KNOT AS A CONTROL CENTER IN MAMMALIAN TOOTH CUSP FORMATION - NONDIVIDING CELLS EXPRESS GROWTH-STIMULATING FGF-4 GENE

The main morphological features of the mammalian tooth crown are cusps , but the developmental mechanisms that cause the formation of cusps a re unknown. Tooth cusp formation commences at cap-stage with the appea rance of the enamel knot, which is a cluster of non-dividing epithelia l cells. In this study, enamel knot was first seen in embryonic mice m olar teeth at the onset of cap-stage. Later in tooth development, seco ndary enamel knot structures were observed at the cusp tips and their appearance corresponded to the formation of individual cusp morphology . Comparisons of the pattern of cell proliferation in embryonic mouse molars and the expression of fibroblast growth factor-4 (Fgf-4) gene r evealed that expression of Fgf-4 mRNA is strictly localized to the non -dividing cells of the enamel knot. However, when FGF-4 protein was in troduced onto isolated dental tissues in vitro, it stimulated the prol iferation of both dental epithelial and mesenchymal cells. Based on th ese results, we suggest that the enamel knot may control tooth morphog enesis by concurrently stimulating cusp growth (via FGF-4 synthesis) a nd by directing folding of cusp slopes (by not proliferating itself).