Editors' ChoiceDevelopment

A Dishevelled paradox

Sci. Signal.  03 Nov 2015:
Vol. 8, Issue 401, pp. ec323
DOI: 10.1126/scisignal.aad7747

Upon binding to a Wnt ligand, the receptor Frizzled (Fz) recruits the scaffold protein Dishevelled (Dsh; also called Dvl) to transduce signaling intracellularly. However, Dsh can also feed back to inhibit signaling in some contexts by inducing phosphorylation of Fz. The nematode Caenorhabditis elegans has three Dsh homologs: DSH-1, DSH-2, and MIG-5. The paired PLM neurons of C. elegans are bipolar; each has a long anterior neurite that grows away from a posterior source of the Wnt homolog LIN-44 and a short posterior neurite that grows toward the source of LIN-44. Zheng et al. found that DSH-1 promotes Wnt signaling in the anterior neurite, while inhibiting signaling in the posterior neurite of PLM neurons. Genetic experiments were consistent with LIN-44 signaling through the Fz homolog LIN-17 to promote outgrowth of the anterior PLM neurite, and this repulsive Wnt signaling was mediated by either of the Dsh homologs DSH-1 or MIG-5. However, DSH-1 and MIG-5 did not function redundantly in outgrowth of the posterior neurite: DSH-1, but not DSH-2 or MIG-5, inhibited LIN-44 signaling in the posterior neurite to allow growth toward the source of LIN-44. DSH-1 was enriched in the posterior neurite compared with the anterior neurite. DSH-1–mediated attenuation of LIN-44 signaling in the posterior neurite required the DEP (disheveled, Egl-10, pleckstrin) domain of DSH-1 and predicted protein kinase C phosphorylation sites in the receptor LIN-17. DSH-1–mediated attenuation of Wnt signaling was also required for posterior-directed outgrowth of other neurons in addition to the PLM neurons, implying that this may be a general mechanism that enables neurons to extend processes toward repulsive Wnt guidance cues. Additional studies will clarify how these paradoxical activities of DSH-1 are controlled.

C. Zheng, M. Diaz-Cuadros, M. Chalfie, Dishevelled attenuates the repelling activity of Wnt signaling during neurite outgrowth in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S. A. 112, 13243–13248 (2015). [PubMed]