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Patients with Axenfeld-Rieger Syndrome (ARS) present various dental abnormalities. ARS is genetically associated with mutations in the PITX2 gene, which encodes one of the earliest transcription factors to initiate tooth development. Thus, Pitx2 has long been considered as an upstream regulator of the transcriptional hierarchy in tooth development. However, it is unclear how its mutant forms cause ARS dental anomalies. In this report, we outline the transcriptional mechanism that is defective in ARS. We demonstrate that during normal tooth development Pitx2 activates Amelogenin (Amel) expression, whose product is required for enamel formation, and that this regulation is perturbed by missense PITX2 mutations found in ARS patients. We further show that Pitx2-mediated Amel activation is enhanced and controlled by co-factors and target genes of Pitx2. These co-factors include cooperative transcription factors such as Dlx2 and FoxJ1; chromatin-associated remodeler factor Hmgn2; and Wnt signaling components such as Lef-1, β-catenin and Dact2. We also unveil a novel Pitx2 target gene Irx1 that functions in dental epithelium differentiation. Consistent with a physiological significance to these modulations, we show that FoxJ1, Dact2, Irx1 knockout mice and K14-Hmgn2 transgenic mice display various types of amelogenesis defects including enamel hypoplasia - consistent with the human ARS phenotype. Collectively, these findings define transcriptional mechanisms and multi-level regulations involved in normal tooth development and shed light on the molecular underpinnings of the enamel defect observed in ARS patients who carry PITX2 mutations. Moreover, our findings validate the etiology of the enamel defect in novel mouse models of enamel hypoplasia. The impact of this study on current understanding of the dental epithelium development and the translational value lie in the gene network we identified. By manipulating components of the network, pluripotent dental cells can be reprogrammed and serve as new source for tooth regeneration. Our findings brought insights of novel gene therapy approach that can alleviate the dental problems of patients with ARS and other developmental anomalies.