Abstract
Cleft palate is one of the most frequent birth defects worldwide. It causes severe problems regarding eating and speaking and requires long-term treatment. Effective prenatal treatment would contribute to reducing the risk of cleft palate. The canonical Wnt signaling pathway is critically involved in palatogenesis, and genetic or chemical disturbance of this signaling pathway leads to cleft palate. Presently, preventative treatment for cleft palate during prenatal development has limited efficacy, but we expect that zebrafish will provide a useful high-throughput chemical screening model for effective prevention. To achieve this, the zebrafish model should recapitulate cleft palate development and its rescue by chemical modulation of the Wnt pathway. Here, we provide proof of concept for a zebrafish chemical screening model. Zebrafish embryos were treated with 12 chemical reagents known to induce cleft palate in mammals, and all 12 chemicals induced cleft palate characterized by decreased proliferation and increased apoptosis of palatal cells. The cleft phenotype was enhanced by combinatorial treatment with Wnt inhibitor and teratogens. Furthermore, the expression of tcf7 and lef1 as a readout of the pathway was decreased. Conversely, cleft palate was prevented by Wnt agonist and the cellular defects were also prevented. In conclusion, we provide evidence that chemical-induced cleft palate is caused by inhibition of the canonical Wnt pathway. Our results indicate that this zebrafish model is promising for chemical screening for prevention of cleft palate as well as modulation of the Wnt pathway as a therapeutic target.
Highlights
Cleft palate and/or lip is one of the most frequent birth defects, occurring in 1 out of 800 to 2500 live births, and induces severe eating and speaking problems, dental defects, ear infections, and hearing loss (Parker et al, 2010; Mezawa et al, 2019)
Non-teratogens (DMSO as vehicle control and isoniazid; INA) and a teratogen that does not induce cleft palate did not induce palate abnormalities (Figures 1C–F,T). These results suggest that specific teratogens induce cleft palate and chemical-induced cleft palate is recapitulated in the zebrafish model
Our results revealed that: (1) Cleft palate in zebrafish was induced by the teratogens
Summary
Cleft palate and/or lip is one of the most frequent birth defects, occurring in 1 out of 800 to 2500 live births, and induces severe eating and speaking problems, dental defects, ear infections, and hearing loss (Parker et al, 2010; Mezawa et al, 2019). The patients require long-term treatments, including surgeries, dental treatment, speech rehabilitation and psychological treatment, which impose huge a lifetime burden estimated at $200,000 on their family and social support system For prenatal prevention and therapy of cleft palate, regulation of such signaling pathways will be a central target. In a mouse model with a consistent cleft palate phenotype, the cleft phenotype is partially or completely recovered by chemical modulation of the canonical Wnt signaling pathway (Liu et al, 2007; Jia et al, 2017; Li et al, 2017)
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