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Craniofacial development is a complex and tightly regulated process and disruptions can lead to structural birth defects, the most common being nonsyndromic cleft lip and palate (NSCLP). Previously, we identifiedFOSas a candidate regulator of NSCLP through family-based association studies, yet its specific contributions to oral and palatal formation are poorly understood. This study investigated the role offosduring zebrafish craniofacial development through genetic disruption and knockdown approaches.Foswas expressed in the periderm, olfactory epithelium and other cell populations in the head. Genetic perturbation offosproduced an abnormal craniofacial phenotype with a hypoplastic oral cavity that showed significant changes in midface dimensions by quantitative facial morphometric analysis. Loss and knockdown offoscaused increased cell apoptosis in the head, followed by a significant reduction in cranial neural crest cells (CNCCs) populating the upper and lower jaws. These changes resulted in abnormalities of cartilage, bone and pharyngeal teeth formation. Periderm cells surrounding the oral cavity showed altered morphology and a subset of cells in the upper and lower lip showed disrupted Wnt/β-catenin activation, consistent with modified inductive interactions between mesenchymal and epithelial cells. Taken together, these findings demonstrate that perturbation offoshas detrimental effects on oral epithelial and CNCC-derived tissues suggesting that it plays a critical role in zebrafish craniofacial development and a potential role in NSCLP.Summary statementPerturbation offos, a candidate gene associated with nonsyndromic cleft lip and palate in humans, causes a distinctive orofacial phenotype in zebrafish as a result of abnormal development of craniofacial tissues. Disruption offosin the oral epithelial, cranial neural crest and Wnt responsive cell populations around the oral cavity causes anomalies that suggest a potential role in the etiology of NSCLP. |
