The local signaling is based on an intercellular feedback loop that has been shown to put Frizzled (Fz) on one side of the cell and keep it from the adjacent side of the neighboring cell. Fz localization is thus propagated from one wing cell to the next. Axelrod's group now shows that the initial polarity of this local pathway is set by global regulators that have thus far been characterized in the eye.
As in the eye, opposing gradients of the cadherin Dachsous (Ds) and a transmembrane protein Four-jointed (Fj) were found in the wing. In both cases, the Ds and Fj gradients activate another cadherin, called Fat (Ft), on the distal sides of the cells where there is more Fj and less Ds. They show that Ds/Ft polarity is necessary for Fz localization, and thus sets the local polarity system. Disruption of the global signal, by mutation of Ds and Ft, produced clones of cells with hairs pointing in a locally organized direction (due to the action of Fz), but the direction was uncoupled from the overall wing axis.
The authors propose that the global pathway, which sets overall direction, is a subtle signal that is prone to cell-to-cell variation. They suggest that deviations are removed through the local Fz pathway, which propagates among neighboring cells to correct errors. Vertebrate systems also exhibit similar precision in polarity—in hair cells in the human ear, for example. Mutations causing deafness syndromes have been mapped to cadherins, suggesting that similar high fidelity mechanisms may be at work. ▪