The mechanisms that underlie morphogenetic cell movements are responsible for many of the most common congenital malformations, including those that impact craniofacial development. There has been circumstantial evidence for many years suggesting that complex carbohydrates play critically important roles during morphogenesis; however, our understanding of their function during mammalian development is limited to anecdotal and descriptive studies. The enzymes responsible for synthesizing complex carbohydrates are the glycosyltransferase, of which there are -150 known polypeptides. Consequently, the current mammalian model systems are inappropriate for detailed analysis of their function, since without more information, there is no way to determine which particular glycosyltransferases are important. This necessitates the development of better model systems to address glycosyltransferase function during development, in general, and during craniofacial morphogenesis, in particular. Towards this end, the zebrafish system proves to be an excellent model system in which to characterize the expression and function of specific glycosyltransferases during development. Preliminary studies demonstrate that specific members of the IS-galactosyl and afucosyltransferases families are expressed during zebrafish embryogenesis, and furthermore, that downregulating their expression leads to severe developmental anomalies, ranging from defects in early embryonic patterning to localized defects in craniofacial development. In this revised renewal application, we will pursue a more detailed analysis of glycosyltransferase expression and function during zebrafish development. Studies will determine if glycosyltransferases participate in defined molecular pathways and/or if they are related to mutations known to affect embryonic development and/or craniofacial morphogenesis. Finally, their mode of action will be examined through traditional biochemical approaches. It is anticipated, that these results will identify glycosyltransferases that play key roles in early embryonic and craniofacial development, and which can then be analyzed in appropriate mammalian model systems.
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