Molecular Genetics Basis of Mammalian Birth Defects

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DESCRIPTION (provided by applicant): Extraembryonic tissues, which are derived from the trophoblast layer of the blastocyst, are crucial for normal mammalian development, with placental failure linked to Intrauterine Growth Retardation syndrome (IUGR) and Preeclampsia. Mutagenesis experiments spanning the last 50 years have uncovered a potential model system for IUGR and/or Preeclampsia. This locus, 17Rn3, lies within the albino-deletion complex on chromosome 7 and consists of 6 alleles (ml-m6), all of which have defects in extraembryonic development that can be attributed to trophoblast-derived abnormalities. These 6 mutants also have primary mesoderm defects in the embryo, indicating that this locus has pleiotropic functions in development. In addition, maternal transmission of the m6 allele in hemizygotes is lethal, suggesting that genomic imprinting could also be involved. Mutation analysis has identified Odz4, the Drosophila Odd Oz homolog 4, as the gene responsible for the m4 allele of 17Rn3. Odz4 is one of the four mouse homologs of the Drosophila odd oz/tenascin major (odz/Ten-m) gene, and a member of the Teneurin protein family. Teneurins are cell surface signaling molecules that are highly expressed in the developing CNS and may play a role in limb development, somite formation and the patterning of neural connections.