Wnt5, A Ligand for Derailed

Abstract

Axons in the developing nervous system respond to guidance cues that either promote chemoattraction or chemorepulsion. The Drosophila nervous system provides a genetically tractable model for studying axonal path-finding. Derailed (Drl), a member of the atypical receptor tyrosine kinase (RYK) family, is necessary and sufficient to direct axons through the anterior commissure (AC); however, the ligand for this receptor has remained elusive (see Garrity). Yoshikawa et al. identified the wnt5 gene in a screen devised to identify mutations that suppressed the loss of AC neurons in Drl mutants. Genetic interaction between wnt5 and drl were further confirmed in flies misexpressing Drl, which can cause posterior commissure (PC) axons to proceed to the anterior commissure (AC). This PC-to-AC switch was suppressed in a wnt5 -deficient mutant. Antibody staining showed that Wnt5 was expressed in the axonal tracts and both the AC and PC. Loss of wnt5 , like loss of drl , caused disorganization of the commissures and loss of AC axonal projections, as well as uncoordinated flies. Ectopic expression of Wnt5 at the midline caused loss of AC formation (which requires midline crossing) consistent with Wnt5 acting as a repulsive signal for the Drl-expressing neurons. Binding of Drl to Wnt5 was confirmed using an epitope-tagged Drl extracellular fragment as a probe, and labeling was lost in wnt5 mutants. Labeling was only observed in the PC despite the presence of Wnt5 in both commissures, possibly because in the AC Drl is already bound to Wnt5, thus making Wnt5 inaccessible to the exogenous probe. The pathway activated by Wnt5 and Drl appears independent of any signaling mediated by Wnt receptors of the Frizzled family, because mutations in genes in the Wnt-Frizzled pathway do not affect Drl-mediated AC to PC switching. These results identify another receptor-ligand interaction important for axon guidance and identify the first ligand for an RYK. P. A. Garrity, How neurons avoid derailment. Nature 422 , 570-571 (2003). [Online Journal] S. Yoshikawa, R. D. McKinnon, M. Kokel, J. B. Thomas, Wnt-mediated axon guidance via the Drosophila Derailed receptor. Nature 422 , 583-588 (2003). [Online Journal]