The molecular mechanism mediating morphogenesis during mammalian embryogenesis are poorly understood. In part this is related to the fact that few mammalian genes known to control specific aspects of morphogenetic development have been cloned and characterized. A family of transgenic mice that has a mutation in a gene essential for normal foot development has recently been identified. The feet of the mutant mice show a congenital syndactyly of the phalanges of the middle toes. The first and fifth toes develop suggesting that the syndactyly is not due to simple inactivation of a structural gene essential for toe separation. Instead, integration of the transgenic DNA may have inactivated and tagged a gene that plays a role in directing morphogenesis or specifying positional information in the developing foot. As initial steps toward investigating that possibility, the specific aims of this research proposal are: 1) to verify that the mice with syndactyly are homozygous for the transgenic insert, 2) to characterize the genome in the region of the transgenic insert, and to look for alterations in the same regions of the genome of allelic mutants, 3) to study the transcript or transcripts that are altered or absent in the mice with syndactyly, and 4) to begin to analyze the role of the altered gene(s) in normal foot development by determining the amino acid sequence(s) of the encoded protein(s), and by characterizing the pattern of transcription of the gene(s) during embryonic development. The proposed experiments include cloning of the genomic sequences flanking the transgenic insert, cloning of the homologous sequences from the wild-type genome and if needed from the allelic mutants, identification of the altered transcriptional unit, cloning of the cDNA, sequencing, and in situ hybridizations. Limb deformities are common human birth defects. This mutant family of transgenic mice represents a model system in which to characterize the molecular basis for a specific birth defect. Such a characterization will provide information about possible causes of similar human birth defects and will hopefully suggest strategies for prevention of such defects. There is a possibility that the inactivated gene plays a role in cell-cell communication and that characterization of its mechanism of action will suggest a model for normal cell-cell interaction during morphogenesis and for the breakdown in a normal cell-cell communication that accompanies cancer formation.

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Baylor College of Medicine
Schools of Medicine
United States
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