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Rib-vertebrae (rv) is an autosomal recessive mutation in mouse that affects somite formation, morphology, and patterning. Expression of Notch pathway components is affected in the paraxial mesoderm of rv mutant embryos, and rv and a null allele of the Notch ligand delta1 show non-allelic non-complementation. By fine genetic mapping and complementation testing we have identified Tbx6, a gene essential for paraxial mesoderm formation, as the gene mutated in rv. Compound heterozygotes carrying a Tbx6 null allele and rv show a phenotype that is milder than in homozygous Tbx6 null but more severe than in homozygous rv mutants. Tbx6 expression is down-regulated in rv mutant embryos. An insertion in the promoter region upstream of the transcriptional start is present in the genome of rv mutants but not in different strains of mice wild type for Tbx6. Our results indicate that rv is a regulatory mutation of Tbx6 causing a hypomorphic phenotype.

Rib-vertebrae (rv) is an autosomal recessive mutation in mouse that affects the morphogenesis of the vertebral column. Axial skeleton defects vary along the anterior-posterior body axis, and include split vertebrae and neural arches, and fusions of adjacent segments. Here, we show that defective somite patterning underlies the vertebral malformations and altered Notch signaling may contribute to the phenotype. Somites in affected regions are irregular in size and shape, epithelial morphology is disrupted, and anterior-posterior somite patterning is abnormal, reminiscent of somite defects obtained in loss-of-function alleles of Notch signaling pathway components. Expression of Dll1, Dll3, Lfng and Notch1 is altered in rv mutant embryos, and rv and Dll1(lacZ), a null allele of the Notch ligand Delta1, genetically interact. Mice double heterozygous for rv and Dll1(lacZ), show vertebral defects, and one copy of Dll1(lacZ) on the homozygous rv background enhances the mutant phenotype and is lethal in the majority of cases. However, fine genetic mapping places rv into an interval on chromosome seven that does not contain a gene encoding a known component of the Notch signaling pathway.