Abstract: The Par-complex is a highly conserved cell polarization machinery, playing critical roles in tissue development and homeostasis. However, how extracellular signals globally orient Par-dependent cell polarity in tissues remains poorly understood. We show here that four of seven Drosophila Wnts redundantly serve as directional cues for the Par-dependent cell polarity of neural stem cells, neuroblasts, through a novel pathway. Wnt2/5/6/D proteins, expressed in ectodermal cells, act via frizzled receptors on underlying neuroblasts to localize armadillo/β-catenin to neuroblast cytocortex facing the Wnt signal source. The localized armadillo recruits the Par complex and Pins complex to the neuroblast apical side, through the association of arm with Par3 and Inscuteable. Wnts consequently orient the cell polarity and asymmetric divisions of neuroblasts perpendicular to the epithelium, allowing nerve tissue to grow inward along the central-peripheral axis in Drosophila embryos. This novel non-canonical Wnt signaling pathway may regulate Par-dependent polarity in various biological contexts.
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