Vertebrate Wnt5a – At the crossroads of cellular signalling

Wnt signalling is an essential pathway in embryogenesis, differentiation, cell motility, development, and adult tissue homeostasis in vertebrates. The Wnt signalling network can activate several downstream pathways such as the β-catenin-dependent TCF/LEF transcription, the Wnt/planar cell polarity (PCP) pathway, and the Wnt/Calcium pathway. Wnt5a is a vertebrate Wnt ligand that is most often associated with the Wnt/PCP signalling pathway. Wnt5a/PCP signalling has a well-described role in embryogenesis via binding to a receptor complex of Frizzled and its co-receptors to initiate downstream activation of the c-Jun N-terminal kinase (JNK) signalling cascade and the Rho and Rac GTPases, Rho-Kinase (ROCK). This activation results in the cytoskeletal remodelling required for cell polarity, migration, and subsequently, tissue re-arrangement and organ formation. This review will focus on more recent work that has revealed new roles for Wnt5a ligands and consequently, an emerging broader function. This is partly due to our growing understanding of the crosstalk between the Wnt/PCP pathway with both the Wnt/β-catenin pathway and other signalling pathways, and in part due to the identification of novel atypical receptors for Wnt5a that demonstrate a far broader role for this ligand.