Wnt Signalling Controls the Response to Mechanical Loading during Zebrafish Joint Development

Joint morphogenesis requires mechanical activity during development. Loss of mechanical strain causes abnormal joint development, which can impact long term joint health. While cell orientation and proliferation are known to shape the joint, dynamic imaging of developing joints in vivo have not been possible in other species. Using genetic labelling techniques in zebrafish we were able, for the first time, to dynamically track cell behaviours in intact moving joints. We identify that proliferation and migration, which contribute to joint morphogenesis, are mechanically controlled and are significantly reduced in immobilised larvae. By comparison to strain maps of the developing skeleton we identify canonical Wnt signalling as a candidate to transduce mechanical forces into joint cell behaviours. We show that in the jaw Wnt signalling is reduced specifically in regions of high strain in response to loss of muscle activity. By pharmacological manipulation of canonical Wnt signalling we demonstrate that Wnt acts downstream of mechanical activity and is required for joint patterning and chondrocyte maturation. Wntl6, independent of muscle activity, controls proliferation and migration, but plays no role in chondrocyte intercalation.