Mice with a transgenic insertional mutation in the Meox1 mesodermal homeodomain transcription factor gene on chromosome 11 show abnormalities in the axial skeleton including cranio-vertebral fusions, vertebro- vertebral fusions, hemivertebrae, and a vertebrogenic spina bifida. These phenotypes can all be traced back to abnormalities in the developing sklerotome. A close relative, Meox2, though initially coexpressed with Meox1, evidently cannot compensate for the lack of Meox1. However, even though the lack of Meox2 alone is compatible with life, mice doubly homozygous for our Meox1 allele and a Meox2 knock-out allele are severely affected as demonstrated in a collaborative effort. Thus, Meox1 and Meox2 are two related mesodermal homeodomain transcription factors that must collaborate to establish the intricate patterning of the axial skeleton. Interestingly, homozygous Meox1 mutant females cannot lactate because of a defect in mammary gland development during late pregnancy. Whether this lactation defect is due to a stromal or an epithelial defect is currently being investigated by mammary gland transplantations. Since the transgenic insertion has resulted in a deletion of genomic DNA beyond the 3' end of the Meox1 gene, it is possible that the skeletal phenotype and/or the mammary gland phenotype are due to effects on one or more than one additional gene located in the vicinity of Meox1. Therefore, we have initiated attempts to rescue the mutant mice with a Meox1 cDNA, using a YAC-based transgenic strategy.
