CDC-42 in polarisation: to be or not to be active

The polarisation of embryonic cells is essential for the execution of developmental programmes, and in many organisms is triggered by polarisation cues that result in an asymmetric localisation of PAR proteins. The activity and localisation of these proteins are controlled by small GTPases of the Rho family. In Caenorhabditis elegans, the establishment of radial polarity requires the Rho GTPase CDC-42 to exclude PAR-6 from sites of cell contact and therefore restrict it to contact-free cell surfaces, but it is not understood how CDC-42 is activated selectively at cell-free surfaces. Emily Chan and Jeremy Nance (p. 1692) aim to answer this question by analysing the functions of the 20 putative C. elegans Rho guanine exchange factors (GEFs) to identify those that activate CDC-42 during radial polarisation. They find that overexpressing either ECT-2 or CGEF-1 is sufficient to activate CDC-42 and to ectopically recruit PAR-6 to sites of cell contacts. However, both of these Rho GEFs localise to contact and contact-free sites at the cell cortex, so how can CDC-42 be activated at contact-free sites only? The authors had previously found that the Rho GTPase-activating protein (GAP) PAC-1 inhibits CDC-42 at cell contacts, and, taken together with the data presented here, this suggests that radial polarisation results from a competition between RhoGEFs, which activate CDC-42 throughout the cortex, and PAC-1, which inactivates it only at cell contact sites.