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 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 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 Hedgehog produced by the Drosophila wing imaginal disc induces distinct responses in three target tissues

Development ◽  
2020 ◽  
Vol 147 (22) ◽  
pp. dev195974
Author(s):  
Ryo Hatori ◽  
Thomas B. Kornberg
Keyword(s):  
Signal Transduction ◽  
Imaginal Disc ◽  
Wing Disc ◽  
Wing Imaginal Disc ◽  
Concentration Gradients ◽  
Anterior Compartment ◽  
Animal Development ◽  
Evolutionarily Conserved ◽  
Cell Type Specific ◽  
Hh Signaling

ABSTRACTHedgehog (Hh) is an evolutionarily conserved signaling protein that has essential roles in animal development and homeostasis. We investigated Hh signaling in the region of the Drosophila wing imaginal disc that produces Hh and is near the tracheal air sac primordium (ASP) and myoblasts. Hh distributes in concentration gradients in the anterior compartment of the wing disc, ASP and myoblasts, and activates genes in each tissue. Some targets of Hh signal transduction are common to the disc, ASP and myoblasts, whereas others are tissue-specific. Signaling in the three tissues is cytoneme-mediated and cytoneme-dependent. Some ASP cells project cytonemes that receive both Hh and Branchless (Bnl), and some targets regulated by Hh signaling in the ASP are also dependent on Bnl signal transduction. We conclude that the single source of Hh in the wing disc regulates cell type-specific responses in three discreet target tissues.

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 Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength

Development ◽  
2021 ◽  
Vol 148 (19) ◽  
Author(s):  
Jennifer H. Kong ◽  
Cullen B. Young ◽  
Ganesh V. Pusapati ◽  
F. Hernán Espinoza ◽  
Chandni B. Patel ◽  
...  
Keyword(s):  
Small Molecules ◽  
Birth Defects ◽  
Birth Defect ◽  
Hedgehog Signaling ◽  
Multiple Birth ◽  
In Utero Exposure ◽  
Membrane Protein Complex ◽  
Protein Target ◽  
Hh Signaling ◽  
Genetic And Environmental Factors

ABSTRACT Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo−/− embryos. Additionally, tissues that develop normally in Mosmo−/− embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.

scholarly journals Osteocalcin expressing cells from tendon sheaths in mice contribute to tendon repair by activating Hedgehog signaling

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Yi Wang ◽  
Xu Zhang ◽  
Huihui Huang ◽  
Yin Xia ◽  
YiFei Yao ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Hedgehog Signaling ◽  
Progenitor Cell ◽  
Tendon Repair ◽  
Tendon Sheath ◽  
Lineage Tracing ◽  
Specific Marker ◽  
Molecular Function ◽  
Hh Signaling ◽  
Necessary And Sufficient

Both extrinsic and intrinsic tissues contribute to tendon repair, but the origin and molecular functions of extrinsic tissues in tendon repair are not fully understood. Here we show that tendon sheath cells harbor stem/progenitor cell properties and contribute to tendon repair by activating Hedgehog signaling. We found that Osteocalcin (Bglap) can be used as an adult tendon-sheath-specific marker in mice. Lineage tracing experiments show that Bglap-expressing cells in adult sheath tissues possess clonogenic and multipotent properties comparable to those of stem/progenitor cells isolated from tendon fibers. Transplantation of sheath tissues improves tendon repair. Mechanistically, Hh signaling in sheath tissues is necessary and sufficient to promote the proliferation of Mkx-expressing cells in sheath tissues, and its action is mediated through TGFβ/Smad3 signaling. Furthermore, co-localization of GLI1+ and MKX+ cells is also found in human tendinopathy specimens. Our work reveals the molecular function of Hh signaling in extrinsic sheath tissues for tendon repair.

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.

Hedgehog Signaling in Animal Development and Human Disease

2000 ◽  
pp. 211-235 ◽  
Author(s):  
E. C. Bailey ◽  
M. P. Scott ◽  
R. L. Johnson
Keyword(s):  
Human Disease ◽  
Hedgehog Signaling ◽  
Animal Development

scholarly journals Mud Loss Restricts Yki-Dependent Hyperplasia in Drosophila Epithelia

2020 ◽  
Vol 8 (4) ◽  
pp. 34
Author(s):  
Amalia S. Parra ◽  
Christopher A. Johnston
Keyword(s):  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Chemical Exchange ◽  
Protein Complexes ◽  
Growth Dynamics ◽  
Secretory Activity ◽  
Wing Disc ◽  
Tissue Growth ◽  
Tissue Type ◽  
Mud Loss

Tissue development demands precise control of cell proliferation and organization, which is achieved through multiple conserved signaling pathways and protein complexes in multicellular animals. Epithelia are a ubiquitous tissue type that provide diverse functions including physical protection, barrier formation, chemical exchange, and secretory activity. However, epithelial cells are also a common driver of tumorigenesis; thus, understanding the molecular mechanisms that control their growth dynamics is important in understanding not only developmental mechanisms but also disease. One prominent pathway that regulates epithelial growth is the conserved Hippo/Warts/Yorkie network. Hippo/Warts inactivation, or activating mutations in Yorkie that prevent its phosphorylation (e.g., YkiS168A), drive hyperplastic tissue growth. We recently reported that loss of Mushroom body defect (Mud), a microtubule-associated protein that contributes to mitotic spindle function, restricts YkiS168A-mediated growth in Drosophila imaginal wing disc epithelia. Here we show that Mud loss alters cell cycle progression and triggers apoptosis with accompanying Jun kinase (JNK) activation in YkiS168A-expressing discs. To identify additional molecular insights, we performed RNAseq and differential gene expression profiling. This analysis revealed that Mud knockdown in YkiS168A-expressing discs resulted in a significant downregulation in expression of core basement membrane (BM) and extracellular matrix (ECM) genes, including the type IV collagen gene viking. Furthermore, we found that YkiS168A-expressing discs accumulated increased collagen protein, which was reduced following Mud knockdown. Our results suggest that ECM/BM remodeling can limit untoward growth initiated by an important driver of tumor growth and highlight a potential regulatory link with cytoskeleton-associated genes.

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