Wnt5a-Ror signaling constitutes a developmental pathway crucial for embryonic tissue morphogenesis, reproduction and adult tissue regeneration, yet the molecular mechanisms by which the Wnt5a-Ror pathway mediates these processes are largely unknown. Using a proteomic screen, we identify the kinesin superfamily protein Kif26b as a downstream target of the Wnt5a-Ror pathway. Wnt5a-Ror, through a process independent of the canonical Wnt/b-catenin-dependent pathway, regulates the cellular stability of Kif26b by inducing its degradation via the ubiquitinproteasome system. Through this mechanism, Kif26b modulates the migratory behavior of cultured mesenchymal cells in a Wnt5a-dependent manner. Genetic perturbation of Kif26b function in vivo caused embryonic axis malformations and depletion of primordial germ cells in the developing gonad, two phenotypes characteristic of disrupted Wnt5a-Ror signaling. These findings indicate that Kif26b links Wnt5a-Ror signaling to the control of morphogenetic cell and tissue behaviors in vertebrates and reveal a new role for regulated proteolysis in noncanonical Wnt5a-Ror signal transduction.
Susman, M. W., Karuna, E. P., Kunz, R. C., Gujral, T. S., Cantú, A. V., Choi, S. S., … Ho, H. Y. H. (2017). Kinesin superfamily protein kif26b links wnt5a-ror signaling to the control of cell and tissue behaviors in vertebrates. ELife, 6. https://doi.org/10.7554/eLife.26509