ACTIVIN IS AN ESSENTIAL EARLY MESENCHYMAL SIGNAL IN TOOTH DEVELOPMENTTHAT IS REQUIRED FOR PATTERNING OF THE MURINE DENTITION

Development of the mammalian tooth has been intensively studied as a m odel system far epithelial/mesenchymal interactions during organogenes is, and progress has been made in identifying key molecules involved i n this signaling. We show that activin PA is expressed in presumptive tooth-germ mesenchyme and is thus a candidate for a signaling molecule in tooth development. Analysis of tooth development in activin beta A mutant embryos shows that incisor and mandibular molar teeth fail to develop beyond the bud stage. Activin PA is thus an essential componen t of tooth development. Development of maxillary molars, however, is u naffected in the mutants. Using tissue recombination experiments we sh ow that activin is required in the mesenchyme prior to bud formation a nd that although activin signaling from mesenchyme to epithelium takes place, mutant epithelium retains its ability to support tooth develop ment, Implantation of beads soaked in activin A, into developing mandi bles, is able to completely rescue tooth development from E11.5, but n ot E12.5 or E13.5, confirming that activin is an early, essential mese nchyme signal required before tooth bud formation. Normal development of maxillary molars in the absence of activin shows a position specifi c role for this pathway in development of dentition. Functional redund ancy With activin B or other TGP beta family members that bind to acti vin receptors cannot explain development of maxillary molars in the mu tants since the activin-signaling pathway appears not to be active in these tooth germs. The early requirement for activin signaling in the mesenchyme in incisor and mandibular molar tooth germs must be carried -out in maxillary molar mesenchyme by other independent signaling path ways.