Odontogenesis or tooth development is a highly regulated process that involves complex epithelial-mesenchymal signaling interactions that lead to cuspal morphogenesis, cell differentiation and the subsequent formation of the specialized matrices of enamel, dentin, cementum and bone. Although studies on tooth epithelial-mesenchymal signaling interactions have greatly increased our understanding of molecules that regulate tooth initiation and early morphogenesis (review: Jernvall and Thesleff, Mech. Dev. 92 (2000) 19), the precise nature of the molecular events controlling late morphogenesis and terminal cytodifferentiation is not known. We have recently reported a unique phenotype involving dentition in mice lacking a functional Runx2 gene (D'Souza et al., Development 126 (1999) 2911). The markedly hypoplastic tooth organs as well as defects in the maturation of ameloblasts and odontoblasts point to an important and non-redundant role for Runx2 in tooth morphogenesis and cytodifferentiation. In order to identify genes that are affected by the absence of Runx2, a cDNA library was generated from Runx2(-/-) and Runx2(+/+) first molar organs. Thus far, our analysis has revealed several tooth-specific downstream target genes of Runx2 that include extracellular matrix proteins, kinases, receptors, growth factors, mitochondrial proteins and transcription molecules. Sequence analysis of 61 differentially expressed genes revealed that 96.03% of the clones matched previously described genes in the GenBank/EBML database and 3.96% did not match any entries in the database. Our preliminary expression analysis of one of the differentially expressed clones which encodes for a zinc finger transcription factor termed Zfp reveals that the gene is temporally regulated during tooth development. In conclusion, we have successfully generated a library enriched in genes expressed in Runx2(+/+) molar tooth organs and performed preliminary studies to assess the role of Zfp in tooth development.