title: UNC-4 antagonizes Wnt signaling to regulate synaptic choice in the C. elegans motor circuit.
abstract: Coordinated movement depends on the creation of synapses between specific neurons in the motor circuit. In C. elegans, this important decision is regulated by the UNC-4 homeodomain protein. unc-4 mutants are unable to execute backward locomotion because VA motor neurons are mis-wired with inputs normally reserved for their VB sisters. We have proposed that UNC-4 functions in VAs to block expression of VB genes. This model is substantiated by the finding that ectopic expression of the VB gene ceh-12 (encoding a homolog of the homeodomain protein HB9) in unc-4 mutants results in the mis-wiring of posterior VA motor neurons with VB-like connections. Here, we show that VA expression of CEH-12 depends on a nearby source of the Wnt protein EGL-20. Our results indicate that UNC-4 prevents VAs from responding to a local EGL-20 cue by disabling a canonical Wnt signaling cascade involving the Frizzled receptors MIG-1 and MOM-5. CEH-12 expression in VA motor neurons is also opposed by a separate pathway that includes the Wnt ligand LIN-44. This work has revealed a transcriptional mechanism for modulating the sensitivity of specific neurons to diffusible Wnt ligands and thereby defines distinct patterns of synaptic connectivity. The existence of comparable Wnt gradients in the vertebrate spinal cord could reflect similar roles for Wnt signaling in vertebrate motor circuit assembly.
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Judsen
authors.initials: J
authors.lastname: Schneider
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Skelton
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Von Stetina
authors.forename: Teije C
authors.initials: TC
authors.lastname: Middelkoop
authors.forename: Alexander
authors.initials: A
authors.lastname: van Oudenaarden
authors.forename: Hendrik C
authors.initials: HC
authors.lastname: Korswagen
authors.forename: David M
authors.initials: DM
authors.lastname: Miller
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D017629:Gap Junctions / Q000378:metabolism; D017238:Genes, Helminth / Q000235:genetics; D006023:Glycoproteins / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D007395:Interneurons / Q000378:metabolism; D008953:Models, Anatomic; D009046:Motor Neurons / Q000378:metabolism*; D009068:Movement / Q000502:physiology; D009415:Nerve Net / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D060490:Receptors, Wnt / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D014157:Transcription Factors; D051153:Wnt Proteins; D060449:Wnt Signaling Pathway
chemical_list: D015415:Biomarkers; C518285:CEH-12 protein, C elegans; D029742:Caenorhabditis elegans Proteins; C117259:Egl-20 protein, C elegans; D006023:Glycoproteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D060490:Receptors, Wnt; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; C073171:unc-4 protein, C elegans; D049452:Green Fluorescent Proteins