This form of planar cell polarity (PCP) achieves a remarkable feat. In the fly eye, for example, two nearby cells can somehow tell which one is closer to the equator (middle) of the eye, and specify the R3 (equatorial) and R4 (polar) fates, accordingly. “This is one of the great puzzles of PCP,” says Simon. “The cells are reading the gradient rather than the absolute values, and sensing the smallest differences.”For that process to have any fidelity, polarity researchers believe that communication between the neighboring cells is essential. “The process is not merely one of cells taking positional values but actively comparing positional values,” says Simon. “In that way, cadherins make sense,” because cell contact is probably needed for the comparison to take place. Furthermore, Simon thinks that differences in cadherin levels between the two cells could provide the information the cells need to sense direction.
Yang and Simon began their investigation with a chance observation of eye polarity defects in a mutant defective for Fat, a cadherin superfamily member. Another cadherin superfamily member, Dachsous, also affects polarity, and is found in a gradient that tapers off close to the eye equator. An opposing gradient is formed by another transmembrane protein called Four-jointed.
The researchers induced patches of mutant cells, and looked for cases where one member of the presumptive R3/R4 pair was mutant and one not. This told them that the gradient molecules were working to induce differences first in Fat function and then in Frizzled signaling. Frizzled is a Wnt receptor, but a ligand that might determine PCP has not been found. Simon now believes that differences in Fat function in neighboring cells might be the crucial switch.
Simon hopes to translate his new genetic clues into a biochemical understanding. He is attempting to reproduce the signaling pathway in cultured cells, and to determine which of the new PCP candidates interact with each other in vitro. ▪