Hayes, M., Naito, M., Daulat, A., Angers, S., and Ciruna, B. (2013) Ptk7 promotes non-canonical Wnt/PCP-mediated morphogenesis and inhibits Wnt/beta-catenin-dependent cell fate decisions during vertebrate development. Development (Cambridge, England). 140(8):1807-1818.
Using zebrafish, we have characterised the function of Protein tyrosine kinase 7 (Ptk7), a transmembrane pseudokinase implicated
in Wnt signal transduction during embryonic development and in cancer. Ptk7 is a known regulator of mammalian neural tube
closure and Xenopus convergent extension movement. However, conflicting reports have indicated both positive and negative roles for Ptk7 in canonical
Wnt/β-catenin signalling. To clarify the function of Ptk7 in vertebrate embryonic patterning and morphogenesis, we generated
maternal-zygotic (MZ) ptk7 mutant zebrafish using a zinc-finger nuclease (ZFN) gene targeting approach. Early loss of zebrafish Ptk7 leads to defects
in axial convergence and extension, neural tube morphogenesis and loss of planar cell polarity (PCP). Furthermore, during
late gastrula and segmentation stages, we observe significant upregulation of β-catenin target gene expression and demonstrate
a clear role for Ptk7 in attenuating canonical Wnt/β-catenin activity in vivo. MZptk7 mutants display expanded differentiation of paraxial mesoderm within the tailbud, suggesting an important role for Ptk7 in
regulating canonical Wnt-dependent fate specification within posterior stem cell pools post-gastrulation. Furthermore, we
demonstrate that a plasma membrane-tethered Ptk7 extracellular fragment is sufficient to rescue both PCP morphogenesis and
Wnt/β-catenin patterning defects in MZptk7 mutant embryos. Our results indicate that the extracellular domain of Ptk7 acts as an important regulator of both non-canonical
Wnt/PCP and canonical Wnt/β-catenin signalling in multiple vertebrate developmental contexts, with important implications
for the upregulated PTK7 expression observed in human cancers.