The complexity of the molecular pathways driving facial morphogenesis predisposes to their frequent disturbance resulting in a series of distressing malformations, the most common of which, occurring with a incidence of 1:500-1:2500 live births, are clefts of the lip and palate. Orofacial clefts have a complex etiology that affords significant opportunities to identify genes and gene-environment interactions, and to dissect the developmental mechanisms underlying fundamental aspects of craniofacial morphogenesis and how these are disrupted in a common birth defect. The overall objective of this project is to develop a four-dimensional (ie. spatio-temporal) atlas of gene expression and cell behavior in the developing lip and palate of two evolutionary divergent species, the chick and the mouse. The primary palate in chick, mouse and man develops using similar morphogenetic processes whereas the secondary palate fuses in the midline in the latter two species, but is naturally cleft in the chick.
Specific aims are: 1. to develop an anatomically annotated, four-dimensional, morphological model of development of the primary and secondary palate in the mouse and chick embryo based on optical projection tomography. 2. To use the four-dimensional models to integrate specific aspects of cell behavior with patterning and signaling information generated via whole-mount in situ hybridization. 3. To perform high-resolution analysis of the transcriptional events involved in TGFbeta3-induced fusion of the secondary palate using micro-array and in situ hybridization analyses of synchronized in vitro palatal organ cultures. 4. To investigate the role of Satb2 in TGFbeta3 signal transduction driving development of the secondary palate using gene targeting technology. The rich datasets generated during this project, which will be stored in a publicly accessible electronic database, will provide a rational basis for the selection of candidate genes for cleft lip and/or cleft palate and will underpin experiments to dissect the molecular cascade of events underlying normal development of the lip and palate
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