The Wnt5a-Ror Signaling Pathway in the Morphogenesis of the Embryo

Abstract

Embryonic development is orchestrated by relatively few conserved core developmental signaling pathways that are used reiteratively to grow, specify and shape all tissues in the body into their final functional forms. The Wnt5a signaling pathway is necessary to shape and extend various tissues during morphogenesis, but how Wnt5a signals within cells has long remained unclear and controversial. Through loss-of-function experiments in mice, we demonstrate that the Ror family of receptors mediates Wnt5a-dependent processes in vivo at multiple stages of embryonic development. Of previously proposed mediators of Wnt5a-Ror signaling, we identify Dishevelled phosphorylation, but not the inhibition of β-catenin-dependent transcription or the activation of the JNK pathway, as a physiological target of Wnt5a-Ror signaling. To further understand the molecular mechanisms underlying Wnt5a-Ror function, we performed a proteomic mass spectrometry screen to identify additional mediators of the Wnt5a-Ror pathway. This screen led to the discovery that Kif26b, an atypical and largely uncharacterized member of the kinesin superfamily, is part of an evolutionarily conserved signaling cassette with Wnt5a and Ror proteins during embryonic development. Interestingly, we found that Kif26b protein exhibits a polarized subcellular localization at the trailing edge of cultured mesenchymal cells and functions to promote the migration of these cells. Wnt5a triggers the degradation of Kif26b by a proteasome-dependent mechanism and negatively regulates cell migration in a Kif26b- dependent manner. Together, these findings identify a new noncanonical Wnt5a-Ror-Kif26b signaling pathway that links extracellular signaling to cytoskeletal changes that influences the movement, polarity and shape of developing tissues, and pathological situations where this signaling may be dysregulated.