Molecular Genetics Basis of Mammalian Birth Defects

描述（由申请人提供）：胚外组织来源于胚泡的滋养层，对正常哺乳动物发育至关重要，胎盘衰竭与宫内生长迟缓综合征（IUGR）和先兆子痫有关。跨越过去50年的突变实验已经发现了IUGR和/或先兆子痫的潜在模型系统。该基因座17 Rn 3位于7号染色体上的白化缺失复合体内，由6个等位基因（m1-m6）组成，所有这些等位基因都具有可归因于滋养层来源的异常的胚外发育缺陷。这6个突变体在胚胎中也有初级中胚层缺陷，表明该位点在发育中具有多效性功能。此外，m6等位基因在半合子中的母体传播是致命的，这表明基因组印记也可能参与其中。突变分析已经鉴定出Odz 4，果蝇Odd Oz同源物4，作为负责17 Rn 3的m4等位基因的基因。Odz 4是果蝇odz/tenascin major（odz/Ten-m）基因的四个小鼠同源物之一，并且是Teneurin蛋白家族的成员。Teneurins是在发育中的CNS中高度表达的细胞表面信号分子，并且可能在肢体发育、体节形成和神经连接的模式化中发挥作用。

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.