post-genomic research on cleft lip and palate by molecular signal analysis

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Cleft lip with or without cleft palate is the most common congenital anomaly in the craniofacial region. Knowledge of the molecular mechanisms behind normal lip fusion can contribute to better intervention and improved functional clinical outcome. Transforming growth factor-3 (TGF-3) has been implicated in lip morpho-genesis. Therefore, we hypothesized that TGF-3 functions during lip fusion through regulation of angiogenesis and mesenchymal cell cycle progression during early developmental stages. To test this hypothesis we used the CL/Fraser mouse model, which has a high incidence of cleft lip. Lips isolated from embryonic day (ED) 11.5 mouse embryos were allowed to develop in serum-free organ cultures in the presence or absence of TGF-3. The lips that developed in these cultures fused in 2 days. The following results were obtained. During normal development, we detected positive immunoreactions for TGF-3 at the site of fusion. We also detected mesenchymal cells that were immunopositive for Flk-1 and CD31,which are markers for endothelial cell precursors. Exogenous TGF-3 accelerated lip fusion in culture. This enhancement was associated with an increase in the number of capillary blood vessels in the lips cultured in the presence of TGF-3,in comparison with controls. In tandem, TGF-3 increased the level of expression of both Flk-1 and CD31. Our data suggest that an elevated level of TGF-3 may promote angiogenesis in developing lips that is mediated by increased Flk-1 and CD31 expression. We also detected increased cyclin Dl expression (a marker for cell proliferation) in the presence of TGF-3,which suggests that TGF-3 promoted cell proliferation. Finally these result disclosed that TGF-3 promoted cell proliferation and angiogenesis in lip mesenchymal tissues. These events led to enhanced lip fusion in the presence of TGF-3.