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• W4237121251 abstract "In this issue of Neuron, Liao et al., 2018Liao C.-P. Li H. Lee H.-H. Chien C.-T. Pan C.-L. Cell-Autonomous Regulation of Dendrite Self-Avoidance by the Wnt Secretory Factor MIG-14/Wntless.Neuron. 2018; 98 (this issue, 320–334)Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar uncover a surprising way that the guidance molecule MIG14/Wntless operates in dendrite self-avoidance in sensorimotor neurons. Not only does MIG14/Wntless not require the soluble cue Wntless, but it can mediate direct cell-cell contact at the plasma membrane. During dendrite tip contact, MIG14/Wntless drives local bursts of WASP-dependent actin filament assembly that facilitate sister dendrite repulsion. In this issue of Neuron, Liao et al., 2018Liao C.-P. Li H. Lee H.-H. Chien C.-T. Pan C.-L. Cell-Autonomous Regulation of Dendrite Self-Avoidance by the Wnt Secretory Factor MIG-14/Wntless.Neuron. 2018; 98 (this issue, 320–334)Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar uncover a surprising way that the guidance molecule MIG14/Wntless operates in dendrite self-avoidance in sensorimotor neurons. Not only does MIG14/Wntless not require the soluble cue Wntless, but it can mediate direct cell-cell contact at the plasma membrane. During dendrite tip contact, MIG14/Wntless drives local bursts of WASP-dependent actin filament assembly that facilitate sister dendrite repulsion. Nothing good ever comes from siblings encroaching on one another’s territory. This is amply demonstrated in the developing nervous system, where local guidance molecules act by repelling the inappropriate incursion of an axonal growth cone, or when axons defasciculate at specific locations to permit branching of a nerve bundle. Defects in the sending or receiving of such repulsive cues can result in mis-wiring of neural circuits (Van Battum et al., 2015Van Battum E.Y. Brignani S. Pasterkamp R.J. Axon guidance proteins in neurological disorders.Lancet Neurol. 2015; 14: 532-546Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). Like axons, dendrites also must follow certain “social” rules governing unwanted contact. During the establishment of neural circuits, dendritic arbors of neurons that receive similar axonal input self-organize to ensure that they thoroughly but non-redundantly cover the available target region. The result is a “tiling” effect whereby dendrites of neighboring neurons, for example, in the vertebrateretina, form a regularly spaced mosaic across the input space (Wässle et al., 1981Wässle H. Peichl L. Boycott B.B. Dendritic territories of cat retinal ganglion cells.Nature. 1981; 292: 344-345Crossref PubMed Scopus (240) Google Scholar). For territory coverage to be maximally efficient, dendrites must also ensure that they do not overlap sister dendrites within their own neuron’s dendritic arbor. Recent advances using both vertebrate and invertebrate model systems have begun to uncover the molecular signaling mechanisms that underlie dendrite self-avoidance between and within cells. For example, protocadherins have been implicated in dendritic tiling, and Down syndrome-associated cell adhesion molecules (DsCAMs) have been implicated both in tiling and in dendrite self-avoidance (Zipursky and Grueber, 2013Zipursky S.L. Grueber W.B. The molecular basis of self-avoidance.Annu. Rev. Neurosci. 2013; 36: 547-568Crossref PubMed Scopus (125) Google Scholar). A new paper in this issue of Neuron furthers our knowledge on the cellular and molecular mechanisms of self-avoidance between sister dendrites by making elegant use of an elegant model neuron, the PVD nociceptor neuron of C. elegans (Liao et al., 2018Liao C.-P. Li H. Lee H.-H. Chien C.-T. Pan C.-L. Cell-Autonomous Regulation of Dendrite Self-Avoidance by the Wnt Secretory Factor MIG-14/Wntless.Neuron. 2018; 98 (this issue, 320–334)Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). These aesthetically beautiful neurons form a “menorah-like” branching pattern of primary, secondary, and tertiary dendrites. Normally, tertiary dendrites that arise (via secondary dendrites) from the same primary dendrite do not overlap each other. Neighboring tertiary dendrites thus form a readily detectable gap of approximately 2 μm between their tips. However, in certain C. elegans mutants, these gaps are absent or greatly reduced in number. Prior genetic studies had identified key players in this self-avoidance phenomenon, the disruption of which results in defects in sensorimotor function (Smith et al., 2010Smith C.J. Watson J.D. Spencer W.C. O’Brien T. Cha B. Albeg A. Treinin M. Miller 3rd, D.M. Time-lapse imaging and cell-specific expression profiling reveal dynamic branching and molecular determinants of a multi-dendritic nociceptor in C. elegans.Dev. Biol. 2010; 345: 18-33Crossref PubMed Scopus (129) Google Scholar). UNC-6, the worm ortholog of the well-studied vertebrate axon guidance cue netrin, and its two known receptors in the worm, UNC-40 (an ortholog of mammalian deleted in colon cancer DCC) and UNC-5, were previously implicated in PVD neuron dendrite self-avoidance (Smith et al., 2012Smith C.J. Watson J.D. VanHoven M.K. Colón-Ramos D.A. Miller 3rd, D.M. Netrin (UNC-6) mediates dendritic self-avoidance.Nat. Neurosci. 2012; 15: 731-737Crossref PubMed Scopus (74) Google Scholar). The initial discovery of netrin, a secreted diffusible molecule, as a cue for self-avoidance in the worm was somewhat unexpected, given that previous examples of dendrite self-avoidance cues in the fruit fly Drosophila were mediated via DsCAMs or other direct cell-cell contact mechanisms (Lefebvre, 2017Lefebvre J.L. Neuronal territory formation by the atypical cadherins and clustered protocadherins.Semin. Cell Dev. Biol. 2017; 69: 111-121Crossref PubMed Scopus (20) Google Scholar). Even so, the repurposing of a secreted molecule in sculpting dendrite morphology is not entirely unprecedented, since it is well-established that axon guidance is shaped by both soluble and stationary cues. However, in contrast to axon guidance, where decades of study in a wide array of model organisms have uncovered dozens of cues and their effectors, the downstream molecular targets and the subcellular morphological mechanisms that underlie dendrite self-avoidance are ripe for discovery. This new study by Liao et al. makes one such discovery and yields a few surprises of its own. Liao and colleagues have now expanded the repertoire of dendrite self-avoidance cues to include the MIG-14/Wntless molecule. This transmembrane molecule had previously been implicated in axon guidance as an upstream regulator of secretion of the Wnt family of signaling molecules. As with netrins, Wnts are a conserved superfamily of secreted proteins that have wide-ranging roles in neuromorphogenesis throughout development (Brafman and Willert, 2017Brafman D. Willert K. Wnt/β-catenin signaling during early vertebrate neural development.Dev. Neurobiol. 2017; 77: 1239-1259Crossref PubMed Scopus (49) Google Scholar). The involvement of MIG-14/Wntless in dendrite self-avoidance was therefore not, in itself, surprising. What was entirely unanticipated is that in the C. elegans PVD neuron MIG-14/Wntless operates in dendrite self-avoidance in a manner that does not involve Wnt signaling. Three lines of evidence provided by Liao et al. support this surprising conclusion: First, none of the Wnt mutants tested, nor any mutants of Frizzled, the canonical Wnt receptor, showed defects in PVD neuron dendrite self-avoidance. Heroically, Liao et al. knocked out all six C. elegans Wnts, individually and in a quintuple mutant, and found no significant loss of dendrite self-avoidance. Second, MIG-14 acted cell autonomously in PVD neurons. Third, and very intriguingly, different domains within the MIG-14 molecule were shown to mediate Wnt secretion versus dendrite self-avoidance. Thus, Liao et al. provide evidence that the previously characterized function of MIG-14/Wntless in Wnt secretion is completely dissociable, both structurally and functionally, from its novel role in dendrite repulsion. Their data implicate a critical leucine-rich motif in the second ectodomain. Indeed, during repulsion MIG-14/Wntless appears to be operating more like a classical cell adhesion molecule, since in vitro pull-down assays using two differentially tagged recombinant MIG-14/Wntless fusion proteins indicated that MIG-14 can be pulled down in complexes with itself. Similarly, expression of recombinant MIG-14 caused insect S2 cells selectively to aggregate. To test whether MIG-14 self-interaction mediates neurite repulsion, Liao et al. next used in situ assays to bolster the idea that MIG-14/Wntless has to be expressed in two cells to mediate their repulsion. The authors used ectopic expression experiments in vivo and found that an mCherry-labeled MIG-14/Wntless molecule could cause de-fasciculation between two different types of neurons that normally fasciculate (i.e., form a nerve bundle, or “fascicle”) to form a ring-like structure. De-fasciculation, which presumably represents neurite repulsion, only occurred when MIG-14/Wntless was expressed in both neurons, but not when expressed in either one alone. Further studies will be needed to determine whether and how MIG-14 indeed interacts directly with itself to mediate repulsion in vivo, but the authors do not believe that this occurs via association of cognate leucine-rich motifs. Another unexpected observation that emerged from the Liao et al. study is the potentially paradoxical behavior of the actin cytoskeleton during dendrite self-repulsion. The authors observed that contact between sister dendrite tips was associated with a local burst of filamentous actin (F-actin) polymerization, as seen in time-lapse movies using the genetically encoded F-actin probe LifeAct::GFP. Studies of neurite outgrowth in both vertebrate and invertebrate organisms have established that neurites extend by polymerizing both actin filaments and microtubules, as well as reorganizing the architecture of these polymers within specific domains of the growth cone (see review by Dent et al., 2011Dent E.W. Gupton S.L. Gertler F.B. The growth cone cytoskeleton in axon outgrowth and guidance.Cold Spring Harb. Perspect. Biol. 2011; 3: a001800Crossref PubMed Scopus (394) Google Scholar). During axon guidance, one popular model holds that polymerization and stabilization of both actin filaments and microtubules within the axon tip (i.e., within the growth cone) are positively regulated by cues that promote neurite outgrowth and negatively regulated by cues that induce either growth cone collapse or repulsion-mediated turning. A regulated increase in F-actin polymerization reportedly precedes and is required for growth cone advance toward an attractive signal (Dent et al., 2011Dent E.W. Gupton S.L. Gertler F.B. The growth cone cytoskeleton in axon outgrowth and guidance.Cold Spring Harb. Perspect. Biol. 2011; 3: a001800Crossref PubMed Scopus (394) Google Scholar). Moreover, guidance cues that repel axons away from a given region induce a net loss of growth cone F-actin, and this can be mimicked by actin assembly inhibitors. Collectively, therefore, many studies of axonal growth cones paint a picture in which actin polymerization promotes and actin depolymerization inhibits protrusion outgrowth. PVD self-avoidance, however, seems to depict the opposite: Liao et al. observed a striking burst of actin polymerization at the tips of protrusions just preceding their retraction from one another. C. elegans mutants that were defective in the genes encoding WSP-1 (an ortholog of mammalian WASP/WAVE) prevented this burst of actin polymerization and also attenuated dendrite self-avoidance. This finding seems counter-intuitive, since WASP/WAVE is well-known as a promotor of actin polymerization, and one might have expected to find that actin polymerization is inhibited as neurites retract. Indeed, logic dictates one might expect a net depolymerization of F-actin as neurites are driven by repulsive cues to pull apart. These observations on the actin cytoskeleton hint at intriguing complexity in how dendrite self-avoidance is orchestrated. It is possible, for example, that the burst of new F-actin creates a barrier that prevents fusions of new membrane vesicles with the plasma membrane, keeping the neurite tips at bay. Alternatively, new actin filaments might partner up with actin motor protein myosin. Such actomyosin-driven contraction is indeed observed in many cellular events. When axonal growth cones advance forward, they use a “clutch-like” mechanism (Short et al. 2016Short C.A. Suarez-Zayas E.A. Gomez T.M. Cell adhesion and invasion mechanisms that guide developing axons.Curr. Opin. Neurobiol. 2016; 39: 77-85Crossref PubMed Scopus (24) Google Scholar). Rearward actomyosin movement, seen as the phenomenon of actin retrograde flow, connects to anchor points that attach to the actin cytoskeleton through transmembrane complexes and thereby anchor it to the extracellular matrix at focal contact sites. This results in the plasma membrane ratcheting forward, much like a car moves forward when the clutch engages the motor and couples it to the rearward movement of wheels along pavement. It’s possible that, in PVD sister dendrite tips, if the actin cytoskeleton is not engaged in focal contact anchorage, its retrograde F-actin flow (i.e., rearward movement), driven by myosin-mediated contractility, might simply carry the whole tip structure backward. Further live-imaging studies, including characterization of F-actin-dependent forces within the PVD neuron, will be required to test these and other hypotheses. In addition, live imaging with superresolution methods may be required to characterize the precise moment of PVD dendrite tip contact in relation to the timing of the F-actin burst. Further evidence rebels against the old idea that actin filament polymerization should favor neurite extension and depolymerization should favor neurite retraction. Liao et al. observed that a loss-of-function mutation in the actin depolymerizing factor UNC-60/cofilin robustly rescued self-avoidance defects, again suggesting that shifting F-actin dynamics toward polymerization favors neurite retraction, not protrusion. Proper neural circuit wiring requires a balance between neurite extension and neurite retraction. It will be fascinating to watch the unfolding of new mechanisms that regulate actin filaments in all their subtle and varied forms. Actin does not polymerize into a single filament type: formins are cellular actin nucleators that promote long, bundled filaments; in contrast, the Arp2/3 complex promotes branched filament networks. How such distinct forms of filament assembly control highly localized events during neurite outgrowth and retraction remain to be fully defined. Meanwhile, this interesting paper by Liao and colleagues reveals new tricks for keeping the growth of the dendritic arbor in check to promote neural circuit fidelity. Cell-Autonomous Regulation of Dendrite Self-Avoidance by the Wnt Secretory Factor MIG-14/WntlessLiao et al.NeuronApril 18, 2018In BriefDendrites from the same neuron display self-avoidance. Liao et al. identify Wntless, a protein that controls Wnt secretion, as a novel self-avoidance molecule. They show that Wntless acts through F-actin rather than Wnt signaling to promote dendrite repulsion. Full-Text PDF Open ArchiveAvoiding Sibling Conflict: Lessons from Dendrite Self-Avoidance in C. elegansShelley HalpainNeuronMay 16, 2018In Brief(Neuron 98, 235–237; April 18, 2018) Full-Text PDF Open Archive" @default.
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• W4237121251 title "Avoiding Sibling Conflict: Lessons from Dendrite Self-Avoidance in C. elegans" @default.
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