A critical event in the fusion of the secondary palate is the disappearance of the medial edge epithelium from the midline. Studies in our laboratory have used cell lineage analysis to trace the fate of the medial edge epithelial cells and document that these cells undergo a phenotypic transitions and remain viable as mesenchymal cells. Investigations of the molecular control of the phenotypic transformation have identified TF-beta3 as an important regulating molecule. Homozygous TGF-beta3 knock-out mice do not fuse in organ culture without supplementation of exogenouse TGF-beta3. These findings have led to the hypothesis, TGF-beta3 is a primary effectors molecule responsible for initiating the program of epithelial-mesenchymal transformation in the palatal shelf medial edge epithelial cells during palatal fusion. This hypothesis will be tested by four Specific Aims; 1. To determine the role of TGF-beta3 in the pattern of expression of cell-type specific phenotypic markers in the MEE during palatogenesis; 2. To characterize the mechanism of TGF-beta3 regulation of the cell cycle and MEE cell proliferation prior to palatal shelf contact and the onset of epithelial-mesenchymal transformations; 3. To examine the intracellular signalling pathway in the MEE following binding of the growth factor to its cell surface receptor; 4. To evaluate TGF-beta3 regulation of matrix metalloproteinases in the mesenchyme underlying the MEE responsible for degradation of the basement membrane. Identification of molecular mechanisms essential to the process of palatal fusion will result in future possible applications to determining the mechanisms underlying human craniofacial birth defects, developing prenatal diagnosis strategies, establishing familial risk of craniofacial birth defects, determining the mechanism of action of craniofacial teratogens and reducing the incidence of human craniofacial birth defects.
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