Development of the preventive fetal medication of which a therapeutic target is improvement of the severity of cleft palate phenotype in the cleft palate model mouse

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It is well known that cleft palate phenotype in humans is varied and widely accepted that the cause of human cleft palate is accountable by"multi-factorial theory". However, almost all the cleft palate phenotype in the cleft palate models using laboratory animals showed complete cleft palate only, so that what kind of factors that produce the phenotypic polymorphism of human cleft palate remains enigmatic and the mechanism underlying phenotypic polymorphism of human cleft palate wait for clarification. This study aimed to demonstrate that the epigenetic modifier produces a variety of cleft palate phenotype by using Tgf-beta 3 knockout C57BL6/J mice, whose homozygous fetuses show complete cleft palate only. Furthermore, this study challenged development of the preventive fetal medication using a DNA methyl transferase inhibitor RG108, of which therapeutic target is improvement of the severity of cleft palate phenotype. By using a newly developed in vitro analytic system, I found that al … More though palatal medial edge epithelial(MEE) cells of Tgf-beta 3-null C57BL6/J mouse fetuses have no ability to bring about epithelial-mesenchymal transformation(EMT) and palate fusion, they can undergo spatially specific EMT and partially fuse to the opposed palate by in vitro medication of a DNA methyltransferase inhibitor RG108.In addition, it was found that when the Tgf-beta 3-null mouse fetuses exposed to RG108 in utero, some of them showed variedly incomplete cleft palates, which is remarkably similar to the cleft palate phenotypes observed in humans. In this experimental model, DNA CG islands in the Igf2r sense promoter region became highly demethylated more than those in the intronic Igf2r antisense promoter region, which esulted in the strong expression of IGF2R in both of the epitheium and mesenchyme of the palatal tissues more than those in controls.Taken those results together, this study provided a new insight into the epigenetic mechanism underlying the cause of phenotypic variation of cleft palate phenotype and suggested, for the first time, the possibility of the preventive fetal medication of which a therapeutic target is improvement of the severity of cleft palate phenotype. Less