Tethered wings

Morata, Ginés; Struhl, Gary

doi:10.1038/nature12848

Cited by 10 publications

(9 citation statements)

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“…In addition, we found that Dll expression is activated only after 84 h AEL (Figure S5), which is past the early Wg expression phase suggested for cellular memory [30]. The contradiction between the two modes of Wg patterning mechanisms requires further study for clarification [56].…”

Section: Discussionmentioning

confidence: 81%

Carrier of Wingless (Cow), a Secreted Heparan Sulfate Proteoglycan, Promotes Extracellular Transport of Wingless

Chang

Sun

2014

PLoS ONE

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Morphogens are signaling molecules that regulate growth and patterning during development by forming a gradient and activating different target genes at different concentrations. The extracellular distribution of morphogens is tightly regulated, with the Drosophila morphogen Wingless (Wg) relying on Dally-like (Dlp) and transcytosis for its distribution. However, in the absence of Dlp or endocytic activity, Wg can still move across cells along the apical (Ap) surface. We identified a novel secreted heparan sulfate proteoglycan (HSPG) that binds to Wg and promotes its extracellular distribution by increasing Wg mobility, which was thus named Carrier of Wg (Cow). Cow promotes the Ap transport of Wg, independent of Dlp and endocytosis, and this function addresses a previous gap in the understanding of Wg movement. This is the first example of a diffusible HSPG acting as a carrier to promote the extracellular movement of a morphogen.

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Section: Discussionmentioning

confidence: 81%

Carrier of Wingless (Cow), a Secreted Heparan Sulfate Proteoglycan, Promotes Extracellular Transport of Wingless

Chang

Sun

2014

PLoS ONE

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“…wg is expressed in complex and transient patterns during development of the wing disc, initially in all cells throughout the wing pouch and subsequently restricted in later stages to the dorsoventral boundary. This feature may have inadvertently resulted in the widespread perdurance of tethered Wg throughout the late larval wing pouch [20], as the NRT-Wg protein may be more stable than wild-type Wg [72]. Thus, it remains possible that a requirement for the long-range action of Wg in the wing disc was masked in previous experiments by the unintended ubiquitous expression of tethered Wg.…”

Section: Discussionmentioning

confidence: 99%

“…If one accepts the conclusion that the long-range action of Wg is essential in the adult intestine but dispensable in the wing disc, then it remains possible that these context-specific NRT-Wg phenotypes result from the inherently unique properties of these different tissues. For example, the Wg-receiving cell population, as measured by Wg target gene activation, extends for at least 60 cell diameters from the MHB in the adult posterior midgut [37], but only 15 to 20 cell diameters from the dorsoventral boundary in the larval wing disc [13,20]. Despite its tethering, NRT-Wg might retain an ability to act over short distances, utilizing previously proposed modes of extracellular transport that include cytonemes [73,74,75,76,77], exosomes [78,79,80,81], or via transcytosis [4,82,83].…”

Section: Discussionmentioning

confidence: 99%

“…However, previous studies demonstrated that Wg target gene expression is restricted to the immediate neighbors of cells expressing NRT-Wg and that target gene activation in cells distant from the Wg source is dependent on their continuous ability to receive Wg. These findings do not support a memory model, which remains a subject of ongoing debate [11,13,20,86]. Importantly, in contrast with the larval wing disc, adult gut development begins with histolysis of the larval gut [87]; both the epithelium and musculature of the adult intestine are largely reformed during pupation [45,88].…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with previous studies [13], these more recent results provided additional evidence supporting the conclusion that NRT-Wg is membrane tethered. Surprisingly however, tethered Wg was fully capable of producing not only normally patterned wings, but also viable adults with nearly normal external morphology, albeit with a reduced wing size and a significant delay in development [19,20]. These unexpected findings challenged the well-accepted tenet that Wnts must be secreted and move from their source of synthesis to distant cells to direct tissue patterning.…”

Section: Introductionmentioning

confidence: 99%

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Essential long-range action of Wingless/Wnt in adult intestinal compartmentalization

et al. 2019

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Signal transduction activated by Wingless/Wnt ligands directs cell proliferation and fate specification in metazoans, and its overactivation underlies the development of the vast majority of colorectal cancers. In the conventional model, the secretion and movement of Wingless to cells distant from its source of synthesis are essential for long-range signaling in tissue patterning. However, this model was upended recently by an unanticipated finding: replacement of wild-type Drosophila Wingless with a membrane-tethered form produced viable adults with largely normal external morphology, which suggested that Wingless secretion and movement are dispensable for tissue patterning. Herein, we tested this foundational principle in the adult intestine, where Wingless signaling gradients coincide with all major boundaries between compartments. We find that the critical roles of Wingless during adult intestinal development, which include regulation of target gene activation, boundary formation, stem cell proliferation, epithelial cell fate specification, muscle differentiation, gut folding, and signaling crosstalk with the Decapentaplegic pathway, are all disrupted by Wingless tethering. These findings provide new evidence that supports the requirement for the direct, long-range action of Wingless in tissue patterning, with relevance for animal development, tissue homeostasis and Wnt-driven disease.

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Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet‐Induced Adiposity

et al. 2023

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Recent genetic evidence has linked WNT downstream mutations to fat distribution. However, the roles of WNTs in human obesity remain unclear.Here, the authors screen all Wnt-related paracrine factors in 1994 obese cases and 2161 controls using whole-exome sequencing (WES) and identify that 12 obese patients harbor the same mutations in RSPO1 (p.R219W/Q) predisposing to human obesity. RSPO1 is predominantly expressed in visceral fat, primarily in the fibroblast cluster, and is increased with adiposity. Mice overexpressing human RSPO1 in adipose tissues develop obesity under a high-fat diet (HFD) due to reduced brown/beige fat thermogenesis. In contrast, Rspo1 ablation resists HFD-induced adiposity by increasing thermogenesis. Mechanistically, RSPO1 overexpression or administration significantly inhibits adipocyte mitochondrial respiration and thermogenesis via LGR4-Wnt/𝜷-catenin signaling pathway. Importantly, humanized knockin mice carrying the hotspot mutation (p.R219W) display suppressed thermogenesis and recapitulate the adiposity feature of obese carriers. The mutation disrupts RSPO1's electrostatic interaction with the extracellular matrix, leading to excessive RSPO1 release that activates LGR4-Wnt/𝜷-catenin signaling and attenuates thermogenic capacity in differentiated beige adipocytes. Therefore, these findings identify that gain-of-function mutations and excessive expression of RSPO1, acting as a paracrine Wnt activator, suppress fat thermogenesis and contribute to obesity in humans.

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Tethered wings

Cited by 10 publications

References 10 publications

Carrier of Wingless (Cow), a Secreted Heparan Sulfate Proteoglycan, Promotes Extracellular Transport of Wingless

Carrier of Wingless (Cow), a Secreted Heparan Sulfate Proteoglycan, Promotes Extracellular Transport of Wingless

Essential long-range action of Wingless/Wnt in adult intestinal compartmentalization

Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet‐Induced Adiposity

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