International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

G11 Strain-Dependent Craniofacial and Neural Tube Defects in Ski-Deficient Mice

Clemencia Colmenares1, Edward Stavnezer2, Stuart Schwartz3, and Natalia Lerner1. 1Dept. of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation; 2Dept. of Biochemistry, and 3Dept. of Genetics, Case Western Reserve University

The ski proto-oncogene encodes a nuclear protein that does not bind to DNA, but has been shown to act as a co-activator or co-repressor of multiple transcription factor families. In vitro overexpression studies have implicated ski in the regulation of pathways that control cellular proliferation and the differentiation of multiple cell lineages. Much of that work has been validated by the analysis of ski-deficient mice, which exhibit a complex phenotype involving abnormalities in several tissues, and differences in penetrance and expressivity of some of the defects. To examine the influence of the genetic background, we have generated congenics carrying the ski-null allele in a C57Bl6 background. As reported previously, the homozygous ski mutation in either a mixed or 129 background results in exencephaly, in addition to homeotic transformations of cervical vertebrae and a defect in skeletal muscle differentiation. Surprisingly, in the C57Bl6 background the ski -/- mice have no neural tube defect, but instead show midline facial clefting, iris coloboma, and polydactyly with nearly 100% penetrance. We have also generated F1 (B6 X 129) ski +/- heterozygotes, and the ski -/- offspring of this F1 intercross show either exencephaly or facial clefting. The frequency of the two phenotypes suggests the existence of at least two modifying loci. The clefting defect in B6 mice is reminiscent of a human syndrome characterized by deletions of varying sizes leading to partial monosomy of chromosome 1p36. A recent reassignment of the human ski gene to this chromosomal location suggests that deletion of ski may be involved in cases of 1p36 deletion, particularly in those that involve midline facial clefts.


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