Enhancer Regulation of OSR2 in Mandibular Incisor Agenesis Susceptibility

Area of Science:

• Genetics
• Developmental Biology
• Oral Biology

Background:

• Congenital absence of mandibular incisors (MIA) is prevalent in Asian populations, impacting oral functions, yet its genetic basis is poorly understood.
• Understanding the genetic etiology of MIA is crucial for addressing its long-term consequences on mastication, speech, and aesthetics.

Purpose of the Study:

• To investigate the genome-wide genetic associations of MIA in a Chinese population.
• To elucidate the molecular mechanisms underlying MIA, focusing on the role of OSR2 and its downstream targets in tooth development.

Main Methods:

• Genome-wide association study (GWAS) in a Chinese cohort to identify MIA-associated variants.
• In vitro functional assays using GATA4 binding to the OSR2 promoter and OSR2 effects on stem cell behavior.
• Zebrafish model to assess the in vivo effects of OSR2 on tooth development.
• Mechanistic studies exploring the interaction between OSR2, CXCR4, and the GPCR pathway.

Main Results:

• A novel enhancer variant, rs71514987, was significantly associated with increased MIA risk (OR=2.18, P=3.62 × 10⁻¹⁹).
• The risk allele (C) at rs71514987 reduces GATA4 binding, upregulating OSR2 expression.
• Elevated OSR2 levels impair stem cell differentiation and migration and cause abnormal pharyngeal tooth development in zebrafish.
• OSR2 directly binds to the CXCR4 promoter, influencing odontogenic differentiation via the GPCR pathway.

Conclusions:

• The study identifies rs71514987 as a significant risk factor for MIA and elucidates a novel molecular pathway involving OSR2 and CXCR4 in tooth development.
• These findings provide critical insights into the genetic and molecular etiology of mandibular incisor agenesis, paving the way for future research and potential interventions.