Zebrafish unplugged reveals a role for muscle-specific kinase homologs in axonal pathway choice.
En route to their target, pioneering motor growth cones repeatedly encounter choice points at which they make pathway decisions. In the zebrafish mutant unplugged, two of the three segmental motor axons make incorrect decisions at a somitic choice point. Using positional cloning, we show here that unplugged encodes a homolog of muscle-specific kinase (MuSK) and that, unlike mammalian MuSK, unplugged has only a limited role in neuromuscular synaptogenesis. We demonstrate that unplugged is transiently expressed in cells adjacent to the choice point and that unplugged signaling before the arrival of growth cones induces changes in the extracellular environment. In addition, we find that the unplugged locus generates three different transcripts. The splice variant 1 (SV1) isoform lacks the extracellular modules essential for agrin responsiveness, and signaling through this isoform mediates axonal pathfinding, independent of the MuSK downstream component rapsyn. Our results demonstrate a new role for MuSK homologs in axonal pathway selection.
Zhang
Jing
J
Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6058, USA.
Lefebvre
Julie L
JL
Zhao
Shuxia
S
Granato
Michael
M
D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D009154:Mutation; D009434:Neural Pathways / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D011950:Receptors, Cholinergic / Q000235:genetics / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology*
D018398:Homeodomain Proteins; C490829:MuSK protein, zebrafish; D011950:Receptors, Cholinergic; D029961:Zebrafish Proteins; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases