UNC-4 antagonizes Wnt signaling to regulate synaptic choice in the C. elegans motor circuit

Abstract

SUMMARYCoordinated 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.

Axin Family of Scaffolding Proteins in Development: Lessons from C. elegans

“…It was found that pry-1 RNAi caused defects in ventral cord neurons, such as branched commissures and abnormal midline crossing. In a separate study, Schneider et al [128] reported that pry-1 acts in a canonical WNT-β-catenin pathway to promote synapse formation of a specific motor neuron, based on results showing that pry-1 mutants enhanced movement defects in animals lacking unc-4 (uncoordinated 4)/Hox function.…”

Characterization of paralogous uncx transcription factor encoding genes in zebrafish

“…The Uncx gene (also known as Uncx4.1 , Phd1 and Chx4 ) encodes a transcription factor containing a paired-type homeodomain homolog to Caenorhabditis elegans UNC-4 homeoprotein (Miller et al, 1992; Rovescalli et al, 1996). The nematode UNC-4 controls synaptic choices of specific motor neurons in the ventral nerve cord by modulating their sensitivity to diffusible Wnt ligands (White et al, 1992; Miller and Niemeyer, 1995; Schneider et al, 2012). In C. elegans and Drosophila melanogaster , UNC-4 orthologs form a repressor complex with UNC-37, homolog of Groucho/TLE transcriptional co-repressor (Pflugrad et al, 1997; Winnier et al, 1999; Giot et al, 2003; Von Stetina et al, 2007).…”

Neuronal Target Identification Requires AHA-1-Mediated Fine-Tuning of Wnt Signaling in C. elegans

“…For example, the C. elegans homeodomain protein UNC-4, together with transcription factors HB9 and Groucho, is involved in the formation of neuronal gap junctions between the interneuron AVA and the motor neuron VA [6]–[9]. A recent study further revealed that UNC-4 antagonizes Wnt signaling to regulate this synaptic choice [10]. In addition, molecules involved in axon guidance play a significant role in the refinement of target identification.…”