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Enhancer regulation of OSR2 in mandibular incisor agenesis susceptibility [RNA-Seq]

ABSTRACT: Mandibular incisors are the most frequently congenitally absent teeth in Asian populations, affecting mastication, speech, aesthetics, and oral and maxillofacial functions over the long term. However, the genetic etiology of mandibular incisor agenesis (MIA) remains obscure. In this study, we conducted the first genome-wide association study on MIA in a Chinese population and identified an enhancer variant rs71514987 associated with an increased risk of MIA (odds ratio = 2.18, 95% confidence interval = 1.83-2.58, P = 3.62×10-19). Functional characterization indicated that rs71514987 C allele reduced the binding affinity of GATA4 to the OSR2 promoter, leading to increased OSR2 expression via remote regulation. Notably, elevated OSR2 levels promoted cell proliferation but diminished cell differentiation, migration, and apoptosis capabilities in stem cells from human exfoliated eciduous teeth (SHED), as well as abnormal development of pharyngeal teeth in zebrafish models. Mechanistic experiments further revealed that OSR2 bound to the promoter region of CXCR4, promoting its transcription level in the GPCR pathway, thereby influencing odontogenic differentiation during tooth development. Our findings provide novel insights into the molecular etiology of MIA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE329253 | GEO | 2026/05/02

REPOSITORIES: GEO

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Project description:Previous studies have suggested that Bmp4 is a key Msx1-dependent mesenchymal odontogenic signal for driving tooth morphogenesis through the bud-to-cap transition. Whereas the bud stage tooth developmental arrest in Msx1-/- mutant mice was accompanied by reduction in mesenchymal Bmp4 mRNA expression, we show that depleting functional Bmp4 mRNAs in the tooth mesenchyme, through neural crest-specific gene inactivation in Bmp4f/f;Wnt1Cre mice, caused mandibular molar developmental arrest at the bud stage but allowed maxillary molars and incisors to develop to mineralized teeth. We show that the Wnt inhibitors Dkk2 and Wif1 were much more abundantly expressed in the mandibular than maxillary molar mesenchyme in wildtype embryos and that Dkk2 expression was significantly unregulated in the tooth mesenchyme in Bmp4f/f;Wnt1Cre embryos. In addition, expression of Osr2, which encodes a zinc finger protein that antagonizes Msx1-mediated activation of odontogenic mesenchyme, is significantly upregulated in the molar mesenchyme in Bmp4f/f;Wnt1Cre embryos. Msx1 heterozygosity enhanced maxillary molar developmental defects whereas Osr2 heterozygosity rescued mandibular first molar morphogenesis in Bmp4f/f;Wnt1Cre mice. Moreover, in contrast to complete lack of supernumerary tooth initiation in Msx1-/-Osr2-/- mutant mice, Osr2-/-Bmp4f/f;Wnt1Cre compound mutant mice exhibit formation and subsequent arrest of supernumerary tooth germs that correlated with down regulation of Msx1 expression in the tooth mesenchyme. Taken together, our data indicate that, while reduction in mesenchymal Bmp4 expression alone could not account for the tooth bud arrest phenotype in Msx1-/- mutant mice, Bmp4 signaling synergizes with Msx1 and antagonizes Osr2 to activate mesenchymal odontogenic activity to drive tooth morphogenesis and sequential tooth formation. E13.5 mouse embryos tooth germs were microdissected by laser capture microdissection (LCM), and the mandibular molar and maxillary molar were separated. 3 pairs of control and mutant samples were pooled for the RNA extraction.

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Enhancer regulation of OSR2 in mandibular incisor agenesis susceptibility [RNA-Seq]

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