MOLECULAR PATHOGENESIS OF CRANIOFACIAL MALFORMATIONS

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Among known teratogens, ethanol represents the greatest public health problem in the U.S., playing an etiological role in approximately 5% of all congenital cardiac, central nervous system, and craniofacial malformations. Despite its enormous significance, little is known regarding the molecular pathogenesis of ethanol embryopathy. Cranial neural-crest derived cells (CNCC) are a major constituent of all developing craniofacial structures. Exposure of chick or mouse embryos to ethanol results in excessive craniofacial development. Increased expression of MSX2 and the signaling molecule BMP4 is associated with developmentally-programmed death of CNCC in the hindbrain. Over-expression of MSX2 results in craniofacial malformations strikingly similar to those associated with ethanol exposure. The goal of this project is to determine whether MSX1, MSX2, and/or BMP4 are involved in the excessive cell death associated with ethanol-induced craniofacial malformations. The Specific Aims are as follows: (1) To determine whether craniofacial malformations in MSX2 transgenic mice result from excessive death of MSX2- over-expressing cells. (2) To determine whether MSX1 over-expression affects survival of CNCC and subsequent craniofacial development in mouse embryos. (3) To determine whether ethanol exposure alters Msx1, Msx2, and/or Bmp4 gene expression in mouse embryos. (4) To determine whether ethanol affects survival of CNCC and subsequent craniofacial development in zebrafish embryos and whether these effects are mediated by BMP4 and/or MSX proteins. (5) To determine whether loss-of-function mutations at the Msx1 or Msx2 locus susceptibility to ethanol- induced craniofacial malformations in mice. (6) To identify genes that are transcriptionally regulated by MSX2 in CNCC of mouse embryos that over-express MSX2 or have been exposed to ethanol in utero. In addition to increasing our understanding of disease pathogenesis and of normal development, the identification of genes involved in this process may ultimately provide a diagnostic method for identifying pregnancies at increased risk for ethanol embryopathy.