title: Osr2 acts downstream of Pax9 and interacts with both Msx1 and Pax9 to pattern the tooth developmental field.
abstract: Mammalian tooth development depends on activation of odontogenic potential in the presumptive dental mesenchyme by the Msx1 and Pax9 transcription factors. We recently reported that the zinc finger transcription factor Osr2 was expressed in a lingual-to-buccal gradient pattern surrounding the developing mouse molar tooth germs and mice lacking Osr2 developed supernumerary teeth lingual to their molars. We report here generation of a gene-targeted mouse strain that allows conditional inactivation of Pax9 and subsequent activation of expression of Osr2 in the developing tooth mesenchyme from the Pax9 locus. Expression of Osr2 from one copy of the Pax9 gene did not disrupt normal tooth development but was sufficient to suppress supernumerary tooth formation in the Osr2(-/-) mutant mice. We found that endogenous Osr2 mRNA expression was significantly downregulated in the developing tooth mesenchyme in Pax9(del/del) mice. Mice lacking both Osr2 and Pax9 exhibited early tooth developmental arrest with significantly reduced Bmp4 and Msx1 mRNA expression in the developing tooth mesenchyme, similar to that in Pax9(del/del) mutants but in contrast to the rescue of tooth morphogenesis in Msx1(-/-)Osr2(-/-) double mutant mice. Furthermore, we found that Osr2 formed stable protein complexes with the Msx1 protein and interacted weakly with the Pax9 protein in co-transfected cells. These data indicate that Osr2 acts downstream of Pax9 and patterns the mesenchymal odontogenic field through protein-protein interactions with Msx1 and Pax9 during early tooth development.
authors.affiliation: Center for Oral Biology and Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.forename: Zunyi
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Maltby
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Lan
authors.forename: Rulang
authors.initials: R
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001483:Base Sequence; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics; D004247:DNA / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D051957:MSX1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D008648:Mesoderm / Q000196:embryology / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009805:Odontogenesis / Q000235:genetics / Q000502:physiology*; D051764:PAX9 Transcription Factor; D051761:Paired Box Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy; D025941:Protein Interaction Mapping; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014083:Tooth Germ / Q000196:embryology / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D051957:MSX1 Transcription Factor; C484084:Msx1 protein, mouse; C438618:Osr2 protein, mouse; D051764:PAX9 Transcription Factor; D051761:Paired Box Transcription Factors; C488759:Pax9 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D004247:DNA