Molecular Genetics Basis of Mammalian Birth Defects

描述(申请人提供)：胚外组织来自胚泡的滋养层，对哺乳动物的正常发育至关重要，胎盘衰竭与宫内生长迟缓综合征(IUGR)和先兆子痫有关。过去50年的突变实验已经发现了一种潜在的IUGR和/或先兆子痫的模型系统。17Rn3位于7号染色体上的白化缺失复合体中，由6个等位基因(m1-m6)组成，这些等位基因都存在胚胎外发育缺陷，可归因于滋养层来源的异常。这6个突变体在胚胎中也存在初级中胚层缺陷，表明该基因座在发育过程中具有多效性。此外，M6等位基因在半合子中的母系传播是致命的，这表明基因组印记也可能参与其中。突变分析确定，果蝇Odd Oz同源基因4 ODZ4是17Rn3的M4等位基因。ODZ4是果蝇odoz/tenascin主要(odz/Ten-m)基因的四个小鼠同源物之一，也是Teneurin蛋白家族的成员。Teneurins是一种细胞表面信号分子，在发育中的中枢神经系统中高度表达，可能在肢体发育、体节形成和神经连接模式中发挥作用。

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.