Editors' ChoiceAxon Guidance

Plugging In Motoneurons

Sci. Signal.  17 Mar 2009:
Vol. 2, Issue 62, pp. ec96
DOI: 10.1126/scisignal.262ec96

During embryonic development, acetylcholine receptors (AChRs) accumulate in clusters at the center of muscle fibers, where they are later joined by a motor axon nerve terminal. This restriction of AChRs to the central muscle zone requires the muscle-specific receptor tyrosine kinase MuSK. In zebrafish, the unplugged locus encodes two splice variants of a MuSK homolog: The full-length (FL) isoform participates in the formation of neuromuscular junctions, whereas the splice variant 1 (SV1) isoform is involved in axonal guidance. Jing et al. found that AChR distribution in zebrafish embryos was diffuse and no longer restricted to the central muscle zone when the embryos were injected with antisense morpholino oligonucleotides to knock down SV1 but not when injected with those that knocked down FL. In unplugged-null zebrafish embryos, the growth cones of motoneurons navigated from the spinal cord to muscle territory in a wider, less well-defined path compared with the paths of motoneurons of wild-type embryos. Because morpholino knockdown of Wnt11r, a member of the family of Wnt ligands, disrupted the central distribution of AChRs and caused motoneuron growth cone phenotypes similar to those seen in unplugged-deficient embryos, the authors suspected that Wnt11r bound to Unplugged. Accordingly, the co-injection of mRNAs encoding Wnt11r and SV1 into zebrafish embryos caused the formation of AChR clusters outside the central muscle zone, an effect that was not observed with the co-injection of mRNAs encoding Wnt11r and an unplugged mutant (SV1ΔCRD) lacking the cysteine-rich domain (CRD), which was identified as the binding site for Wnt11r. As had been previously demonstrated for the mammalian homologs, Unplugged interacted with the Wnt intracellular effector Dishevelled, and overexpression in a subset of muscle cells of a truncated form of Dishevelled that inhibits downstream Wnt signaling recapitulated the growth cone pathfinding defects seen in unplugged-null embryos. The authors propose a model in which Wnt11r activates Dishevelled through the SV1 isoform of Unplugged to restrict AChR distribution and guide motoneuron growth cones.

L. Jing, J. L. Lefebvre, L. R. Gordon, M. Granato, Wnt signals organize synaptic prepattern and axon guidance through the zebrafish unplugged/MuSK receptor. Neuron 61, 721–733 (2009). [Online Journal]