scholarly journals Hherisomes, hedgehog specialized recycling endosomes, are required for high level hedgehog signaling and tissue growth

2021 ◽  
Author(s):  
Sandrine Pizette ◽  
Tamás Matusek ◽  
Bram Herpers ◽  
Pascal P. Thérond ◽  
Catherine Rabouille
Keyword(s):  
Hedgehog Signaling ◽  
Wing Disc ◽  
Tissue Growth ◽  
Small Gtpase ◽  
Recycling Endosomes ◽  
Drosophila Wing ◽  
Immuno Electron Microscopy ◽  
Wing Imaginal Discs ◽  
Hh Signaling ◽  
High Level

In metazoans, tissue growth and patterning is partly controlled by the Hedgehog (Hh) morphogen. Using immuno-electron microscopy on Drosophila wing imaginal discs, we identified a cellular structure, the Hherisomes that contain the majority of intracellular Hh. Hherisomes are recycling tubular endosomes and their formation is specifically boosted by overexpression of Hh. Expression of Rab11, a small GTPase involved in recycling endosomes, boosts the size of Hherisomes and their Hh concentration. Conversely, increased expression of the transporter Dispatched, a regulator of Hh secretion, leads to their clearance. We show that increasing Hh density in Hherisomes through Rab11 overexpression enhances both the level of Hh-signaling and disc pouch growth, whereas Dispatched overexpression decreases high level Hh-signaling and growth. We propose that upon secretion, a pool of Hh triggers low level signaling, whereas a second pool of Hh is endocytosed and recycled through Hherisomes to stimulate high level signaling and disc pouch growth. Altogether our data indicate that Hherisomes are required to sustain physiological Hh activity necessary for patterning and tissue growth in the wing disc.

scholarly journals Hedgehog signaling can enhance glycolytic ATP production in the Drosophila wing disc

2021 ◽  
Author(s):  
Ioannis Nellas ◽  
K. Venkatesan Iyer ◽  
Juan M. Iglesias-Artola ◽  
André Nadler ◽  
Natalie A. Dye ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Energy Production ◽  
Wing Disc ◽  
Tissue Growth ◽  
Atp Production ◽  
Animal Development ◽  
Genetic Perturbations ◽  
Steady State Levels ◽  
Hh Signaling ◽  
Metabolic Behavior

ABSTRACTEnergy production and utilization is critically important for animal development and growth. How it is regulated in space and time during tissue growth remains largely unclear. Toward this end, we used a FRET-based adenosine triphosphate (ATP) sensor to dynamically monitor ATP levels across a growing tissue, using the Drosophila wing disc. We discovered that steady-state levels of ATP are spatially uniform across the wing pouch. Pharmacologically inhibiting oxidative phosphorylation, however, reveals spatial heterogeneities in metabolic behavior, whereby signaling centers at compartment boundaries produce more ATP from glycolysis than the rest of the tissue. Genetic perturbations indicate that the conserved Hedgehog (Hh) signaling pathway can enhance ATP production by glycolysis. Collectively, our work reveals a positive feedback loop between Hh signaling and energy metabolism, advancing our understanding of the connection between conserved developmental patterning genes and energy production during animal tissue development.

scholarly journals Membrane potential regulates Hedgehog signaling and compartment boundary maintenance in the Drosophila wing disc

2020 ◽  
Author(s):  
Maya Emmons-Bell ◽  
Riku Yasutomi ◽  
Iswar K. Hariharan
Keyword(s):  
Membrane Potential ◽  
Hedgehog Signaling ◽  
Membrane Depolarization ◽  
Wing Disc ◽  
Anterior Compartment ◽  
Drosophila Wing ◽  
Compartment Boundary ◽  
Boundary Maintenance ◽  
Elevated Expression ◽  
Hh Signaling

AbstractThe Drosophila wing imaginal disc is composed of two lineage-restricted populations of cells separated by a smooth boundary. Hedgehog (Hh) from posterior cells activates a signaling pathway in anterior cells near the boundary which is necessary for boundary maintenance. Here, we show that membrane potential is patterned in the wing disc. Anterior cells near the boundary, where Hh signaling is most active, are more depolarized than posterior cells across the boundary. Elevated expression of the ENaC channel Ripped Pocket (Rpk), observed in these anterior cells, requires Hh. Antagonizing Rpk reduces depolarization and disrupts the compartment boundary. Using genetic and optogenetic manipulations, we show that membrane depolarization promotes membrane localization of Smoothened and augments Hh signaling. Thus, membrane depolarization and Hh-dependent signaling mutually reinforce each other in this region. Finally, clones of depolarized cells survive preferentially in the anterior compartment and clones of hyperpolarized cells survive preferentially in the posterior compartment.

scholarly journals Oligomerization and endocytosis of Hedgehog is necessary for its efficient exovesicular secretion

2015 ◽  
Vol 26 (25) ◽  
pp. 4700-4717 ◽  
Author(s):  
Anup Parchure ◽  
Neha Vyas ◽  
Charles Ferguson ◽  
Robert G. Parton ◽  
Satyajit Mayor
Keyword(s):  
Cell Surface ◽  
Long Range ◽  
Imaginal Discs ◽  
Multivesicular Bodies ◽  
Selective Effect ◽  
Endosomal Sorting ◽  
Drosophila Wing ◽  
Dependent Process ◽  
Wing Imaginal Discs ◽  
Hh Signaling

Hedgehog (Hh) is a secreted morphogen involved in both short- and long-range signaling necessary for tissue patterning during development. It is unclear how this dually lipidated protein is transported over a long range in the aqueous milieu of interstitial spaces. We previously showed that the long-range signaling of Hh requires its oligomerization. Here we show that Hh is secreted in the form of exovesicles. These are derived by the endocytic delivery of cell surface Hh to multivesicular bodies (MVBs) via an endosomal sorting complex required for transport (ECSRT)–dependent process. Perturbations of ESCRT proteins have a selective effect on long-range Hh signaling in Drosophila wing imaginal discs. Of importance, oligomerization-defective Hh is inefficiently incorporated into exovesicles due to its poor endocytic delivery to MVBs. These results provide evidence that nanoscale organization of Hh regulates the secretion of Hh on ESCRT-derived exovesicles, which in turn act as a vehicle for long-range signaling.

Role of knot (kn) in Wing Patterning in Drosophila

Genetics ◽  
1997 ◽  
Vol 147 (3) ◽  
pp. 1203-1212 ◽  
Author(s):  
Katerina Nestoras ◽  
Helena Lee ◽  
Jym Mohler
Keyword(s):  
Hedgehog Signaling ◽  
Imaginal Disc ◽  
Hedgehog Signaling Pathway ◽  
Posterior Compartment ◽  
Drosophila Wing ◽  
Compartment Boundary ◽  
Hh Signaling ◽  
Embryonic Segmentation ◽  
Anterior Posterior

We have undertaken a genetic analysis of new strong alleles of knot (kn). The original kn1 mutation causes an alteration of wing patterning similar to that associated with mutations of fused (fu), an apparent fusion of veins 3 and 4 in the wing. However, unlike fu, strong kn mutations do not affect embryonic segmentation and indicate that kn is not a component of a general Hh (Hedgehog)-signaling pathway. Instead we find that kn has a specific role in those cells of the wing imaginal disc that are subject to ptc-mediated Hh-signaling. Our results suggest a model for patterning the medial portion of the Drosophila wing, whereby the separation of veins 3 and 4 is maintained by kn activation in the intervening region in response to Hh-signaling across the adjacent anterior-posterior compartment boundary.

scholarly journals Chondroitin sulfate proteoglycan Windpipe modulates Hedgehog signaling in Drosophila

2018 ◽  
Author(s):  
Masahiko Takemura ◽  
Fredrik Noborn ◽  
Jonas Nilsson ◽  
Eriko Nakato ◽  
Tsu-Yi Su ◽  
...  
Keyword(s):  
Cell Surface ◽  
Chondroitin Sulfate ◽  
Hedgehog Signaling ◽  
Transmembrane Protein ◽  
Wing Disc ◽  
Chondroitin Sulfate Proteoglycan ◽  
Growth Factor Signaling ◽  
Sulfate Proteoglycan ◽  
Sugar Chain ◽  
Hh Signaling

AbstractProteoglycans, a class of carbohydrate-modified proteins, often modulate growth factor signaling on the cell surface. However, the molecular mechanism by which proteoglycans regulate signal transduction is largely unknown. In this study, using a recently-developed glycoproteomic method, we found that Windpipe (Wdp) is a novel chondroitin sulfate proteoglycan (CSPG) in Drosophila. Wdp is a single-pass transmembrane protein with leucin-rich repeat (LRR) motifs and bears three CS sugar chain attachment sites in the extracellular domain. Here we show that Wdp modulates the Hedgehog (Hh) pathway. Overexpression of wdp inhibits Hh signaling in the wing disc, which is dependent on its CS chains and the LRR motifs. Conversely, loss of wdp leads to the upregulation of Hh signaling. Furthermore, knockdown of wdp increase the cell surface accumulation of Smoothened (Smo), suggesting that Wdp inhibits Hh signaling by regulating Smo stability. Our study demonstrates a novel role of CSPG in regulating Hh signaling.

scholarly journals Dynamic Interpretation of Hedgehog Signaling in the Drosophila Wing Disc

PLoS Biology ◽  
2009 ◽  
Vol 7 (9) ◽  
pp. e1000202 ◽  
Author(s):  
Marcos Nahmad ◽  
Angelike Stathopoulos
Keyword(s):  
Hedgehog Signaling ◽  
Wing Disc ◽  
Drosophila Wing ◽  
Dynamic Interpretation

scholarly journals Lipoproteins carry endocannabinoids that inhibit the Hedgehog pathway

2013 ◽  
Author(s):  
Helena Khaliullina ◽  
Mesut Bilgin ◽  
Julio L. Sampaio ◽  
Andrej Shevchenko ◽  
Suzanne Eaton
Keyword(s):  
Mass Spectrometry ◽  
Hedgehog Signaling ◽  
Hedgehog Signaling Pathway ◽  
Cubitus Interruptus ◽  
Drosophila Wing ◽  
Lipid Mass ◽  
Biochemical Fractionation ◽  
Wing Imaginal Discs ◽  
Hedgehog Proteins

Hedgehog proteins are lipid-modified secreted signaling molecules that regulate tissue development and homeostasis. Lipids contained in circulating lipoproteins repress the Hedgehog signaling pathway in the absence of Hedgehog ligand, but the identity of these lipids is unknown. Here, using biochemical fractionation and lipid mass spectrometry, we identify these inhibitory lipids as endocannabinoids. Endocannabinoids are present in lipoproteins of both flies and humans, and repress the pathway in both mammalian signaling assays and Drosophila wing imaginal discs. In Drosophila, endocannabinoids are required in vivo to keep the levels of Smoothened and full-length Cubitus interruptus (Ci155) low in the absence of Hedgehog. Furthermore, elevating their endogenous levels inhibits Hedgehog-dependent accumulation of Smoothened and Ci155. Interestingly, cannabis-derived phytocannabinoids are also potent pathway inhibitors in flies and mammals. These findings constitute a novel link between organismal metabolism and local Hedgehog signaling, and suggest previously unsuspected mechanisms for the broad physiological activities of cannabinoids.

scholarly journals Competition between two phosphatases fine-tunes Hedgehog signaling

2020 ◽  
Vol 220 (2) ◽  
Author(s):  
Min Liu ◽  
Aiguo Liu ◽  
Jie Wang ◽  
Yansong Zhang ◽  
Yajuan Li ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Phosphatase Activity ◽  
Protein Phosphatase ◽  
Hedgehog Signaling ◽  
Catalytic Subunit ◽  
Regulatory Subunit ◽  
Feedback Mechanisms ◽  
Hh Signaling ◽  
High Level ◽  
Signaling Activity

Hedgehog (Hh) signaling is essential for embryonic development and adult homeostasis. How its signaling activity is fine-tuned in response to fluctuated Hh gradient is less known. Here, we identify protein phosphatase V (PpV), the catalytic subunit of protein phosphatase 6, as a homeostatic regulator of Hh signaling. PpV is genetically upstream of widerborst (wdb), which encodes a regulatory subunit of PP2A that modulates high-level Hh signaling. We show that PpV negatively regulates Wdb stability independent of phosphatase activity of PpV, by competing with the catalytic subunit of PP2A for Wdb association, leading to Wdb ubiquitination and subsequent proteasomal degradation. Thus, regulated Wdb stability, maintained through competition between two closely related phosphatases, ensures graded Hh signaling. Interestingly, PpV expression is regulated by Hh signaling. Therefore, PpV functions as a Hh activity sensor that regulates Wdb-mediated PP2A activity through feedback mechanisms to maintain Hh signaling homeostasis.

Quantitative EM of gap junction distribution in mutant drosophila wing discs

1983 ◽  
Vol 41 ◽  
pp. 720-721
Author(s):  
J.S. Ryerse
Keyword(s):  
Gap Junctions ◽  
Growth Control ◽  
Intercellular Junctions ◽  
Wing Disc ◽  
En Bloc ◽  
Metabolic Cooperation ◽  
Drosophila Wing ◽  
Adult Wing ◽  
Wing Discs ◽  
Wing Pouch

Gap junctions are intercellular junctions found in both vertebrates and invertebrates through which ions and small molecules can pass. Their distribution in tissues could be of critical importance for ionic coupling or metabolic cooperation between cells or for regulating the intracellular movement of growth control and pattern formation factors. Studies of the distribution of gap junctions in mutants which develop abnormally may shed light upon their role in normal development. I report here the distribution of gap junctions in the wing pouch of 3 Drosophila wing disc mutants, vg (vestigial) a cell death mutant, 1(2)gd (lethal giant disc) a pattern abnormality mutant and 1(2)gl (lethal giant larva) a neoplastic mutant and compare these with wildtype wing discs.The wing pouch (the anlagen of the adult wing blade) of a wild-type wing disc is shown in Fig. 1 and consists of columnar cells (Fig. 5) joined by gap junctions (Fig. 6). 14000x EMs of conventionally processed, UA en bloc stained, longitudinally sectioned wing pouches were enlarged to 45000x with a projector and tracings were made on which the lateral plasma membrane (LPM) and gap junctions were marked.

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