Release and spread of Wingless is required to pattern the proximo-distal axis of Drosophila renal tubules

Beaven, Robin; Denholm, Barry

doi:10.7554/elife.35373

Cited by 26 publications

(36 citation statements)

References 92 publications

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“…Although Wg has been characterised as a diffusible ligand, acting on a range of several cells, it was reported that the substitution of the wg locus by a membrane tethered version of Wg (NRT-Wg) gives rise to flies that develop apparently normally (although poorly viable), with no overt morphological phenotypes, suggesting that a long range action by diffusion of Wg may not be required during development (Piddini and Vincent, 2009). However, some studies using the NRT-Wg Drosophila line have shown that Wg signalling at a distance is required in specific contexts (Beaven and Denholm, 2018). Here we show that short-range diffusion of Wg is indeed required for the appropriate patterning of the wing margin, as initially reported.…”

Section: Discussionsupporting

confidence: 83%

Pegasus, a small extracellular peptide regulating the short-range diffusion of Wingless

Magny

Pueyo

Bishop

et al. 2019

Preprint

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Small Open Reading Frames (smORFs) coding for peptides of less than 100 amino-acids are emerging as a fundamental and pervasive gene class, found in the hundreds of thousands in metazoan genomes. Even though some of these genes are annotated, their function, if any, remains unknown. Here we characterize the function of a smORF encoding a short 80 aa peptide, pegasus (peg), which facilitates Wg diffusion during the development of the Drosophila wing imaginal disc. During wing development, Wg has sequential functions, and in the later stages, when peg is strongly expressed, it patterns the presumptive wing margin. A reduction in Wg protein secretion at this stage produces effects ranging from total abolition of the wing margin to partial loss of bristles and reduction of proneural gene expression. Here we show that the Peg peptide enhances the short-range of Wg diffusion in this context, in order to produce a proper wing margin. We show that CRISPR/Cas9-mediated mutations of pegasus generate wing margin phenotypes, and changes in target gene expression, consistent with a role in Wg signalling. We find that Peg is secreted, and that it co-localizes and coimmunoprecipitates with Wg, suggesting that Peg directly binds Wg in order to enhance its extracellular transport and signalling, and our data from fixed and in-vivo Wg gradient measurements supports a model in which this diffusion enhancement may rely on the stabilization of extracellular Wg. Our results unveil a new element in the regulation of the Wg signalling pathway, and shed light on the functional consequences of the miss-regulation of Wg diffusion in this developmental context, while also reminding us of the functional diversity, and relevance of small open reading frame genes.

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Section: Discussionsupporting

confidence: 83%

Pegasus, a small extracellular peptide regulating the short-range diffusion of Wingless

Magny

Pueyo

Bishop

et al. 2019

Preprint

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“…The need for secreted Wg has been recently challenged, with Wg tethering to the membrane (NRT-wg) showing Wg secretion to be largely dispensable for development (Alexandre et al, 2014). In contrast, other recent studies suggest that Wg release and spreading is necessary (Beaven and Denholm, 2018;Pani and Goldstein, 2018;Stewart et al, 2019). We find tethering Wg at the NMJ synapse increases extracellular Wg ligand levels, with no change in mature bouton numbers.…”

Section: Discussionmentioning

confidence: 56%

Carrier of Wingless (Cow) Regulation ofDrosophilaNeuromuscular Junction Development

Kopke

Leahy

Vita

et al. 2020

eNeuro

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The first Wnt signaling ligand discovered, Drosophila Wingless [Wg (Wnt1 in mammals)], plays critical roles in neuromuscular junction (NMJ) development, regulating synaptic architecture, and function. Heparan sulfate proteoglycans (HSPGs), consisting of a core protein with heparan sulfate (HS) glycosaminoglycan (GAG) chains, bind to Wg ligands to control both extracellular distribution and intercellular signaling function. Drosophila HSPGs previously shown to regulate Wg trans-synaptic signaling at the NMJ include the glypican Dally-like protein (Dlp) and perlecan Terribly Reduced Optic Lobes (Trol). Here, we investigate synaptogenic functions of the most recently described Drosophila HSPG, secreted Carrier of Wingless (Cow), which directly binds Wg in the extracellular space. At the glutamatergic NMJ, we find that Cow secreted from the presynaptic motor neuron acts to limit synaptic architecture and neurotransmission strength. In cow null mutants, we find increased synaptic bouton number and elevated excitatory current amplitudes, phenocopying presynaptic Wg overexpression. We show cow null mutants exhibit an increased number of glutamatergic synapses and increased synaptic vesicle fusion frequency based both on GCaMP imaging and electrophysiology recording. We find that membranetethered Wg prevents cow null defects in NMJ development, indicating that Cow mediates secreted Wg signaling. It was shown previously that the secreted Wg deacylase Notum restricts Wg signaling at the NMJ, and we show here that Cow and Notum work through the same pathway to limit synaptic development. We conclude Cow acts cooperatively with Notum to coordinate neuromuscular synapse structural and functional differentiation via negative regulation of Wg trans-synaptic signaling within the extracellular synaptomatrix.

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“…Development of the MTs occurs during embryogenesis and they are completely functional by the first instar larval stage. The development and physiology of the fly renal tubule have been extensively investigated and reviewed in previous publications (Beyenbach et al, 2010;Denholm, 2013;Skaer, 1996;Dow, 2012;Beaven and Denholm, 2018;Bunt et al, 2010). Each tubule is composed of different segments (ureter, main, initial and transitional segments) that are functionally and genetically distinct (Chintapalli et al, 2012), and has two main epithelial cell types: the principal cell (PC) and the stellate cell (SC) (Dow, 2012;Denholm et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Novel roles for GATAe in growth, maintenance and proliferation of cell populations in the Drosophila renal tubule

et al. 2019

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The GATA family of transcription factors is implicated in numerous developmental and physiological processes in metazoans. In Drosophila melanogaster, five different GATA factor genes (pannier, serpent, grain, GATAd and GATAe) have been reported as essential in the development and identity of multiple tissues, including the midgut, heart and brain. Here, we present a novel role for GATAe in the function and homeostasis of the Drosophila renal (Malpighian) tubule. We demonstrate that reduced levels of GATAe gene expression in tubule principal cells induce uncontrolled cell proliferation, resulting in tumorous growth with associated altered expression of apoptotic and carcinogenic key genes. Furthermore, we uncover the involvement of GATAe in the maintenance of stellate cells and migration of renal and nephritic stem cells into the tubule. Our findings of GATAe as a potential master regulator in the events of growth control and cell survival required for the maintenance of the Drosophila renal tubule could provide new insights into the molecular pathways involved in the formation and maintenance of a functional tissue and kidney disease.

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Release and spread of Wingless is required to pattern the proximo-distal axis of Drosophila renal tubules

Cited by 26 publications

References 92 publications

Pegasus, a small extracellular peptide regulating the short-range diffusion of Wingless

Pegasus, a small extracellular peptide regulating the short-range diffusion of Wingless

Carrier of Wingless (Cow) Regulation ofDrosophilaNeuromuscular Junction Development

Novel roles for GATAe in growth, maintenance and proliferation of cell populations in the Drosophila renal tubule

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