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OBJECTIVE Epigenetic regulation plays important role in stem cell maintenance. Ptip was identified as epigenetic regulator, but the role in dental progenitor cells remains unclear. SUBJECTS AND METHODS Dental mesenchymal progenitor cells were targeted by Sp7-icre and visualized in mTmG; Sp7-icre mice. The Ptipf/f ; Sp7-icre mice were generated and the phenotype of incisors and molars were shown by micro-computerized tomography, scanning electron microscope, htoxylin & eosin staining and immunofluorescence. Dental mesenchymal progenitor cells were sorted by fluorescence-activated cell sorting from lower incisors and RNA-sequencing was performed. RESULTS The Sp7-icre targets dental mesenchymal progenitor cells in incisors and molars. The Ptipf/f ; Sp7-icre mice showed spontaneous fractures in the cusp of upper incisors and lower incisors at three weeks (w), compensative overgrowth of lower incisors at one month (M), and overgrowth extended to the outside at 2 M. The molars showed shortened roots. The functions of odontoblasts and dental mesenchymal progenitor cells were impaired. Mechanically, loss of Ptip activates the Wnt pathway and upregulates the expression of Wls in dental mesenchymal progenitor cells. Also, the regenerative ability of lower incisors was significantly impaired. CONCLUSION We firstly demonstrated that Ptip was crucial for tooth development via regulating Wnt signaling.