title: Syd/JIP3 and JNK signaling are required for myonuclear positioning and muscle function.
abstract: Highlighting the importance of proper intracellular organization, many muscle diseases are characterized by mispositioned myonuclei. Proper positioning of myonuclei is dependent upon the microtubule motor proteins, Kinesin-1 and cytoplasmic Dynein, and there are at least two distinct mechanisms by which Kinesin and Dynein move myonuclei. The motors exert forces both directly on the nuclear surface and from the cell cortex via microtubules. How these activities are spatially segregated yet coordinated to position myonuclei is unknown. Using Drosophila melanogaster, we identified that Sunday Driver (Syd), a homolog of mammalian JNK-interacting protein 3 (JIP3), specifically regulates Kinesin- and Dynein-dependent cortical pulling of myonuclei without affecting motor activity near the nucleus. Specifically, Syd mediates Kinesin-dependent localization of Dynein to the muscle ends, where cortically anchored Dynein then pulls microtubules and the attached myonuclei into place. Proper localization of Dynein also requires activation of the JNK signaling cascade. Furthermore, Syd functions downstream of JNK signaling because without Syd, JNK signaling is insufficient to promote Kinesin-dependent localization of Dynein to the muscle ends. The significance of Syd-dependent myonuclear positioning is illustrated by muscle-specific depletion of Syd, which impairs muscle function. Moreover, both myonuclear spacing and locomotive defects in syd mutants can be rescued by expression of mammalian JIP3 in Drosophila muscle tissue, indicating an evolutionarily conserved role for JIP3 in myonuclear movement and highlighting the utility of Drosophila as a model for studying mammalian development. Collectively, we implicate Syd/JIP3 as a novel regulator of myogenesis that is required for proper intracellular organization and tissue function.
authors.affiliation: Cell and Developmental Biology, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York, United States of America; Program in Developmental Biology, Sloan-Kettering Institute, New York, New York, United States of America.
authors.forename: Victoria K
authors.initials: VK
authors.lastname: Schulman
authors.affiliation: Program in Developmental Biology, Sloan-Kettering Institute, New York, New York, United States of America.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Folker
authors.affiliation: Program in Developmental Biology, Sloan-Kettering Institute, New York, New York, United States of America.
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Rosen
authors.affiliation: Cell and Developmental Biology, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York, United States of America; Program in Developmental Biology, Sloan-Kettering Institute, New York, New York, United States of America.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Baylies
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002467:Cell Nucleus / Q000648:ultrastructure*; D029721:Drosophila Proteins / Q000502:physiology*; D004331:Drosophila melanogaster; D004398:Dyneins / Q000378:metabolism; D016547:Kinesins / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000502:physiology*; D032342:Muscle Cells / Q000378:metabolism* / Q000648:ultrastructure; D009132:Muscles / Q000166:cytology / Q000502:physiology; D021381:Protein Transport
chemical_list: D002352:Carrier Proteins; D029721:Drosophila Proteins; D008565:Membrane Proteins; C417671:syd protein, Drosophila; D004398:Dyneins; D016547:Kinesins