Genetic determinants of teratogen-induced abnormal development in mouse and rat embryos in vitro.

The response of an embryo to a teratogenic treatment is often critically dependent on its genetic makeup. However, in conventional in vivo studies of gene-teratogen interactions it may be difficult to distinguish between the effects of genes that are carried by the embryo and those that are carried by the mother. It is likewise not easy to determine whether an observed interaction is between a particular gene and the parent compound administered, or whether it is with a metabolite that has been generated by the maternal system.

DNA methyltransferase in normal and Dnmtn/Dnmtn mouse embryos.

The mouse genome experiences a large decrease in net 5-methylcytosine between fertilization and implantation; de novo methylation brings 5-methylcytosine to adult somatic cell levels between implantation and gastrulation. Very little is known of the regulation of demethylation or de novo methylation. Levels of the one known form of DNA methyltransferase are very high in early embryos, but the enzyme is localized to the cytoplasm during most of preimplantation development.

Nhlh1, a basic helix-loop-helix transcription factor, is very tightly linked to the mouse looptail (Lp) mutation.

Looptail (Lp) is a mutation on the distal portion of mouse Chromosome (Chr) 1 that affects neurulation in mouse and is phenotypically expressed by appearance of an open neural tube along the entire antero-posterior axis of the embryo (craniorachischisis). Nhlh1, a member of the basic helix-loop-helix family of transcription factors, is expressed in the developing neural tube in structures affected by the Lp mutation and has been regionally assigned to the distal part of mouse Chr 1. Using a large panel of looptail animals from an (Lp/+ x SWR/J)F1 x SWR/J segregating backcross progeny, we have determined that Nhlh1 maps very close to Lp, with no recombinant detected in 500 informative animals tested; both map within a 0.

High-resolution linkage map in the vicinity of the Lp locus.

Looptail (Lp) is a mutation that profoundly affects neurulation in mouse and is characterized by craniorachischisis, an open neural tube extending from the midbrain to the tail in embryos homozygous for the mutation. Lp maps to the distal portion of mouse chromosome 1, and as part of a positional cloning approach, we have generated a high-resolution linkage map of the Lp chromosomal region. For this, we have carried out extensive segregation analysis in a total of 706 backcross mice informative for Lp and derived from two crosses, (Lp/+ x SJL/J)F1 x SJL/J and (Lp/+ x SWR/J) F1 x SWR/J.