Cellular and molecular mechanisms that shape the development and evolution of tail vertebral proportion in mice and jerboas

Limbs and vertebrae elongate by endochondral ossification, but local growth control is highly modular, such that not all bones are the same length. Compared to limbs, which have a different evolutionary and developmental origin, far less is known about how individual vertebrae establish proportion. Using the jerboa and mouse tail skeletons, we find that cell number is a common driver of limb and vertebral proportion in both species. However, chondrocyte hypertrophy, which is a major driver of proportion in all mammal limbs, is limited to the extreme disproportionate growth of jerboa mid-tail vertebrae. The genes associated with differential growth in the vertebral skeleton overlap significantly, but not substantially, with genes associated with limb proportion. Among shared candidates, loss of Natriuretic Peptide Receptor 3 in mice causes disproportionate elongation of the proximal and mid-tail vertebrae, in addition to the proximal limb. Our findings, therefore, reveal cellular processes that tune the growth of individual vertebrae while also identifying natriuretic peptide signaling among genetic control mechanisms that shape the entire skeleton.