Wnt signaling establishes anteroposterior neuronal polarity and requires retromer inC. elegans

Abstract

Secreted Wnt proteins influence neural connectivity by regulating axon guidance, dendritic morphogenesis and synapse formation. We report a new role for Wnt and Frizzled proteins in establishing the anteroposterior polarity of the mechanosensory neurons ALM and PLM in C. elegans. Disruption of Wnt signaling leads to a complete inversion of ALM and PLM polarity: the anterior process adopts the length, branching pattern and synaptic properties of the wild-type posterior process, and vice versa. Different but overlapping sets of Wnt proteins regulate neuronal polarity in different body regions. Wnts act directly on PLM via the Frizzled LIN-17. In addition, we show that they are needed for axon branching and anteriorly directed axon growth. We also find that the retromer, a conserved protein complex that mediates transcytosis and endosome-to-Golgi protein trafficking, plays a key role in Wnt signaling. Deletion mutations of retromer subunits cause ALM and PLM polarity, and other Wnt-related defects. We show that retromer protein VPS-35 is required in Wnt-expressing cells and propose that retromer activity is needed to generate a fully active Wnt signal.

-Catenin-Dependent Wnt Signaling in C. elegans: Teaching an Old Dog a New Trick

“…Wnts function in several developmental processes along the anterior-posterior axis during larval development, functioning in cell-fate specification, neuronal migration, and neuronal cell polarity (Eisenmann 2005). For several of these larval Wnt-dependent processes, the Wnt genes also display functional redundancy, such that strong phenotypes are only apparent when multiple Wnt genes are mutated (Zinovyeva and Forrester 2005;Gleason et al 2006;Hilliard and Bargmann 2006;Pan et al 2006;Prasad and Clark 2006;Green et al 2008;Yamamoto et al 2011). This indicates that while in some C. elegans processes, distinct Wnt and Wnt receptor pairings may be used; in other processes, the identity of individual Wnts may not be as important as the reception of a threshold amount of Wnt signal.…”

Wnts as ligands: processing, secretion and reception

“…In yeast, a cluster of proteins termed the retromer complex directs endosome-to-Golgi retrieval of proteins and in vertebrate systems the retromer complex functions in basal-to-apical transcytosis (Verges et al, 2004). Recently, two groups have independently shown that the C. elegans ortholog of the yeast retromer complex subunit Vps35p is required for the long-range signaling capabilities of Egl-20 (C. elegans Wnt ortholog) (Coudreuse et al, 2006;Prasad and Clark, 2006). Mutation in vps35 leads to defects in Wnt-mediated posterior lateral microtubule (PLM) mechanosensory neuron polarity as well as Q neuroblast migration.…”

“…In addition, when retromer function is abolished by vps-26-and vps-35-null mutations, the mutant phenotype appears less severe than Wnt-null mutants suggesting that not all of the signaling functions of C. elegans Wnts (i.e. short-range) are impaired (Prasad and Clark, 2006).…”

Tri sélectif et recyclage

“…Le retromer a été initialement identifié chez la levure comme étant requis pour le routage intracellulaire des hydrolases vacuolaires [17]. Chez le nématode, la perte de fonction du retromer induit des phénotypes restreints observables dans la partie postérieure de l'animal, et similaires à ceux qu'entraîne une altération de la voie de signalisation WNT [14,19]. On observe notamment une inversion de polarité dans la migration antéro-postérieure de certains neurones [14] et l'extension asymétrique de prolongements neuronaux [19].…”

“…Chez le nématode, la perte de fonction du retromer induit des phénotypes restreints observables dans la partie postérieure de l'animal, et similaires à ceux qu'entraîne une altération de la voie de signalisation WNT [14,19]. On observe notamment une inversion de polarité dans la migration antéro-postérieure de certains neurones [14] et l'extension asymétrique de prolongements neuronaux [19]. Des études de mosaïcisme (voir Glossaire) ont montré que le retromer était spécifiquement requis dans les cellules qui sécrètent WNT.…”