Oligosyndactyly (Os) is a radiation-induced mutation located on mouse chromosome 8. In heterozygous mice (Os/+), the mutation results in syndactyly, diabetes insipidus (due to a reduction in size of the kidney) and muscular anomalies. Because of its effects on limb morphogenesis, Os heterozygous mice provide an interesting model of a class of human mutations which result in syndactyly and for which no mechanisms are known. When present in the homozygous state (Os/Os), the mutation is lethal very early in development. Although homozygous embryos are able to hatch from the zona pellucida and form blastocyst outgrowths (the in vitro equivalent to implantation), cells begin to accumulate in mitosis after the fifth to sixth cell division (early blastocyst stage). Even though the cytological appearance is that of mitotic cells treated with a microtubule inhibitor, the homozygous embryo do in fact have normal appearing intact mitotic spindles. These results define the Os mutation as one which, in the homozygous state, prevents the movement of chromosomes from the metaphase plate of intact mitotic spindles. It is the first mammalian developmental mutation to be so defined and is unique among all mitotic arrest mutation so far described in higher eukaryotes. The relationship between the effects found in heterozygous mice with the mitotic arrest that occurs in homozygous embryos remains unknown. The goal of the work outlined in this proposal is to resolve the question concerning the nature of the mitotic arrest and to apply this information to the study of Os-induced syndactyly. The experiments presented constitute a morphological and molecular comparison of Os/Os arrested spindles with those from wild-type embryos. In addition, initial experiments are outlined for examining limb buds from Os/+ mice for mitotic abnormalities. The results obtained from these studies will provide important information on normal mitotic function as well as on how mutant genes affect limb development.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD019892-04
Application #
3317500
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1984-07-01
Project End
1989-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
4
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106