Trans-Synaptic Transmission of Vesicular Wnt Signals through Evi/Wntless
ABSTRACT Wnts play pivotal roles during development and in the mature nervous system. However, the mechanism by which Wnts traffic between cells has remained elusive. Here we demonstrate a mechanism of Wnt transmission through release of exosome-like vesicles containing the Wnt-binding protein Evenness Interrupted/Wntless/Sprinter (Evi/Wls/Srt). We show that at the Drosophila larval neuromuscular junction (NMJ), presynaptic vesicular release of Evi is required for the secretion of the Wnt, Wingless (Wg). We also show that Evi acts cell-autonomously in the postsynaptic Wnt-receiving cell to target dGRIP, a Wg-receptor-interacting protein, to postsynaptic sites. Upon Evi loss of function, dGRIP is not properly targeted to synaptic sites, interfering with postsynaptic Wnt signal transduction. These findings uncover a previously unknown cellular mechanism by which a secreted Wnt is transported across synapses by Evi-containing vesicles and reveal trafficking functions of Evi in both the Wnt-producing and the Wnt-receiving cells. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.
- SourceAvailable from: Stanislav S Zakharenko
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- "Rat cortical neuron cultures secrete exosomes in response to neuronal activity (Faure et al., 2006). Studies in fruit flies have shown that both presynaptic and postsynaptic neurons can interact through exosomal release and subsequent endocytosis (Koles et al., 2012; Korkut et al., 2009, 2013). Furthermore, a recent study has identified various RNA species in neuronal exosomes (Morel et al., 2013), indicating that neuronal exosomes, like exosomes released from other cell types, carry ncRNAs. "
ABSTRACT: Advancing age is associated with the loss of cognitive ability and vulnerability to debilitating mental diseases. Although much is known about the development of cognitive processes in the brain, the study of the molecular mechanisms governing memory decline with aging is still in its infancy. Recently, it has become apparent that most of the human genome is transcribed into non-coding RNAs (ncRNAs) rather than protein-coding mRNAs. Multiple types of ncRNAs are enriched in the central nervous system, and this large group of molecules may regulate the molecular complexity of the brain, its neurons, and synapses. Here, we review the current knowledge on the role of ncRNAs in synaptic plasticity, learning, and memory in the broader context of the aging brain and associated memory loss. We also discuss future directions to study the role of ncRNAs in the aging process.Ageing research reviews 09/2014; 17. DOI:10.1016/j.arr.2014.03.004 · 7.63 Impact Factor
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- "EVs released from neurons have been confirmed as being involved in synaptic function (Faure et al. 2006), with their release being stimulated by enhanced glutamatergic activity and resulting in increased spontaneous neuronal activity with the presence of glutamate receptor 2 subunits in EVs (Lachenal et al. 2011). Furthermore, EVs have been shown to regulate the synaptic transfer of Wnt morphogens at the neuromuscular junction (Korkut et al. 2009), hinting at a potential role in broader Wnt-mediated developmental processes. Additionally, EVs are implicated in various mechanisms within the specialised immune system of the brain (Cossetti et al. 2012). "
ABSTRACT: Multicellular organisms rely upon diverse and complex intercellular communications networks for a myriad of physiological processes. Disruption of these processes is implicated in the onset and propagation of disease and disorder, including the mechanisms of senescence at both cellular and organismal levels. In recent years, secreted extracellular vesicles (EVs) have been identified as a particularly novel vector by which cell-to-cell communications are enacted. EVs actively and specifically traffic bioactive proteins, nucleic acids, and metabolites between cells at local and systemic levels, modulating cellular responses in a bidirectional manner under both homeostatic and pathological conditions. EVs are being implicated not only in the generic aging process, but also as vehicles of pathology in a number of age-related diseases, including cancer and neurodegenerative and disease. Thus, circulating EVs-or specific EV cargoes-are being utilised as putative biomarkers of disease. On the other hand, EVs, as targeted intercellular shuttles of multipotent bioactive payloads, have demonstrated promising therapeutic properties, which can potentially be modulated and enhanced through cellular engineering. Furthermore, there is considerable interest in employing nanomedicinal approaches to mimic the putative therapeutic properties of EVs by employing synthetic analogues for targeted drug delivery. Herein we describe what is known about the origin and nature of EVs and subsequently review their putative roles in biology and medicine (including the use of synthetic EV analogues), with a particular focus on their role in aging and age-related brain diseases.Biogerontology 06/2014; 16(2). DOI:10.1007/s10522-014-9510-7 · 3.01 Impact Factor
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- "Heparan sulfate proteoglycans (HSPGs) of the glypican family, such as Dally and Dally-like protein (Dlp), allow the transfer of WNT from cell to cell, acting as a co-receptor for the ligand, thus allowing the formation of a gradient of WNT activity at a distance from the secreting cells (Yan and Lin, 2009). WNTs can also travel on membranous particles, called argosomes (Panáková et al., 2005), or within exosome-like vesicles (Korkut et al., 2009). Finally, although not formally demonstrated for WNTs, it is also possible that WNTs are transported at a distance similarly to Sonic hedgehog and the TGFβ family member Decapentaplegic, in which the receiving cells grow long cytoplasmic extensions that directly contact morphogensecreting cells (Hsiung et al., 2005; Sanders et al., 2013). "
ABSTRACT: In amniotes, it is widely accepted that WNTs secreted by the dorsal neural tube form a concentration gradient that regulates early somite patterning and myotome organization. Here we demonstrate in the chicken embryo that WNT protein is not secreted to act at a distance, but rather loaded onto migrating neural crest cells that deliver it to somites. Inhibiting neural crest migration or ablating their population has a profound impact on the WNT response in somites. Furthermore, we show that a central player in the efficient delivery of WNT to somites is the heparan sulfate proteoglycan GPC4, expressed by neural crest. Together, our data describe a novel mode of signaling whereby WNT proteins hitch a ride on migratory neural crest cells to pattern the somites at a distance from its source.Development 05/2014; 141(10):2057-63. DOI:10.1242/dev.107656 · 6.27 Impact Factor