Transgenic human HOXB1-9 directs anterior-posterior axial skeleton pattern in Hoxb1-9 deficient mice

Abstract

The cervical and anterior thoracic regions of mammals generally exhibit similar vertebral numbers and identities along the anterior-posterior axis. The position of the forelimbs along the axial skeleton is also generally conserved. In contrast, the number of lumbar and sacral vertebrae and pelvic position exhibit more variation, correlating with posture and locomotion. The molecular mechanisms that lead to these conserved and variable axial skeletal patterns between species are not fully understood. Here we use a human HOXB1-9 transgene to complement a HoxB1-9 deficiency in the mouse. In TgHOXB1-9 mice, human HOXB1, B2, B3, and B4 (HOXB1-4) genes were expressed in mouse embryos in patterns similar to mouse Hoxb1-4 genes. Human transgene expression rescued the cervical and anterior thoracic vertebral patterning defects of HoxB1-9^Δ/Δ mice. In addition, the posterior shift in forelimb position of HoxB1-9^Δ/Δ mice was rescued by the transgene. Interestingly, the position of the lumbar-sacral transition in both TgHOXB1-9; HoxB1-9^Δ/Δ and TgHOXB1-9; HoxB1-9^+/+ mice was altered from six lumbar and four sacral vertebrae found in wild-type controls to five lumbar and five sacral vertebrae. The change in the position of the lumbar-sacral transition consequently altered the position of the pelvis. In contrast to the conserved expression of human HOXB1-4 genes in TgHOXB1-9 mouse embryos, the anterior border of human HOXB9 expression in the neural tube and paraxial mesoderm was shifted posteriorly by 2–3 somites compared to the anterior boundary of endogenous Hoxb9 expression. These findings suggest that conservation and variation in Hoxb/HOXB expression contributes to conserved and species-specific vertebral pattern and limb position.