A β-Catenin-Dependent Wnt Pathway Mediates Anteroposterior Axon Guidance in C. elegans Motor Neurons

Abstract

BackgroundWnts are secreted glycoproteins that regulate diverse aspects of development, including cell proliferation, cell fate specification and differentiation. More recently, Wnts have been shown to direct axon guidance in vertebrates, flies and worms. However, little is known about the intracellular signaling pathways downstream of Wnts in axon guidance.Methodology/Principal FindingsHere we show that the posterior C. elegans Wnt protein LIN-44 repels the axons of the adjacent D-type motor neurons by activating its receptor LIN-17/Frizzled on the neurons. Moreover, mutations in mig-5/Disheveled, gsk-3, pry-1/Axin, bar-1/β-catenin and pop-1/TCF, also cause disrupted D-type axon pathfinding. Reduced BAR-1/β-catenin activity in D-type axons leads to undergrowth of axons, while stabilization of BAR-1/β-catenin in a lin-23/SCFβ-TrCP mutant results in an overextension phenotype.Conclusions/SignificanceTogether, our data provide evidence that Wnt-mediated axon guidance can be transduced through a β-catenin-dependent pathway.

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

“…Studies in C. elegans have revealed roles for these components in cell migration, axon guidance, synaptogenesis and cell fate determination (Zinovyeva and Forrester, 2005;Goldstein et al, 2006;Hilliard and Bargmann, 2006;Pan et al, 2006;Klassen and Shen, 2007;Green et al, 2008;Maro et al, 2009;Song et al, 2010;Harterink et al, 2011). Our results parallel the finding that multiple Wnts and receptors might contribute to each of these features (Zinovyeva et al, 2008).…”

Dishevelled attenuates the repelling activity of Wnt signaling during neurite outgrowth in Caenorhabditis elegans

“…For the above reasons and because all other neurons affected by the loss of Wnt signals only show outgrowth, and not polarity defects (7,11,12), we feel that the defects in the PLM neurons are best described as alterations in outgrowth. Although we could not completely rule out the polarity model, the primary wild-type function of Wnt and Fzd appears to be the stimulation of anterior neurite outgrowth and the inhibition of posterior neurite outgrowth.…”

“…Wnt proteins repel axons expressing the receptor tyrosine kinase Derailed/Ryk (2,3) or the Frizzled (Fzd, Fz) receptor (4)(5)(6)(7)(8)(9), but also act as attractive cues for neurite outgrowth and dendritic formation through the Fzd receptor (10)(11)(12). Moreover, Wnt proteins can promote axon outgrowth and at the same time induce repulsive turning in cultured cortical neurons (6).…”

“…Although the canonical pathway (7,15) and the Wnt/calcium pathway (16) regulate axon guidance in a few instances, Wnt-mediated axon pathfinding mainly uses the PCP pathway, which activates the small GTPases Rho, Rac, and Cdc42, which regulate cytoskeletal dynamics (17,18). Studies from mice, Drosophila, and Caenorhabditis elegans collectively suggest that the core components of PCP signaling involved in axon guidance are the Wnt receptor Fzd, the phosphoprotein Dishevelled (Dsh, Dvl), the transmembrane protein Van Gogh/ Strabismus (Vang/Stbm, Vangl) and its adaptor Prickle (Prkl, Pk), and the atypical cadherin Flamingo/starry night (Fmi/Stan, Celsrs), although the requirement for each component may depend on the specific neuron type (17,19).…”

The Genetics of Axon Guidance and Axon Regeneration in Caenorhabditis elegans

“…egl-20, which is expressed in the posterior of the animal, seems to act as repellent in this case (Pan et al 2006). The Wnts LIN-44 and EGL-20 control the termination point of the DD6 axon in the dorsal nerve cord, which overextend in lin-44 single and lin-44; egl-20 double mutants (Maro et al 2009). For the PQR dendrite, LIN-44 acts as attractive cue, as ectopic expression of lin-44 leads to a reorientation of the dendrite toward the source of expression (Kirszenblat et al 2011).…”