A Feed-Forward Circuit Linking Wingless, Fat-Dachsous Signaling, and the Warts-Hippo Pathway to Drosophila Wing Growth

Transforming growth factor β (TGF-β) signaling plays a fundamental role in metazoan development and tissue homeostasis. However, the molecular mechanisms concerning the ubiquitin-related dynamic regulation of TGF-β signaling are not thoroughly understood. Using a combination of proteomics and an siRNA screen, we identify pVHL as an E3 ligase for SMAD3 ubiquitination. We show that pVHL directly interacts with conserved lysine and proline residues in the MH2 domain of SMAD3, triggering degradation. As a result, the level of pVHL expression negatively correlates with the expression and activity of SMAD3 in cells, Drosophila wing, and patient tissues. In Drosophila, loss of pVHL leads to the up-regulation of TGF-β targets visible in a downward wing blade phenotype, which is rescued by inhibition of SMAD activity. Drosophila pVHL expression exhibited ectopic veinlets and reduced wing growth in a similar manner as upon loss of TGF-β/SMAD signaling. Thus, our study demonstrates a conserved role of pVHL in the regulation of TGF-β/SMAD3 signaling in human cells and Drosophila wing development.

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Boundary Dpp promotes growth of medial and lateral regions of the Drosophila wing

eLife ◽

10.7554/elife.22013 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 14

Author(s):

Lara Barrio ◽

Marco Milán

Keyword(s):

Temperature Sensitive ◽

Drosophila Wing ◽

Compartment Boundary ◽

Absolute Requirement ◽

Proliferative Growth ◽

Graded Activity ◽

Tissue Size ◽

Wing Growth ◽

Intense Debate

The gradient of Decapentaplegic (Dpp) in the Drosophila wing has served as a paradigm to characterize the role of morphogens in regulating patterning. However, the role of this gradient in regulating tissue size is a topic of intense debate as proliferative growth is homogenous. Here, we combined the Gal4/UAS system and a temperature-sensitive Gal80 molecule to induce RNAi-mediated depletion of dpp and characterise the spatial and temporal requirement of Dpp in promoting growth. We show that Dpp emanating from the AP compartment boundary is required throughout development to promote growth by regulating cell proliferation and tissue size. Dpp regulates growth and proliferation rates equally in central and lateral regions of the developing wing appendage and reduced levels of Dpp affects similarly the width and length of the resulting wing. We also present evidence supporting the proposal that graded activity of Dpp is not an absolute requirement for wing growth.

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Faculty Opinions recommendation of Recruitment of cells into the Drosophila wing primordium by a feed-forward circuit of vestigial autoregulation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1089100.543517 ◽

2007 ◽

Author(s):

Ken Irvine

Keyword(s):

Feed Forward ◽

Drosophila Wing

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Faculty Opinions recommendation of Recruitment of Jub by α-catenin promotes Yki activity and Drosophila wing growth.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.734885523.793578172 ◽

2020 ◽

Author(s):

Emmanuel Farge

Keyword(s):

Drosophila Wing ◽

Wing Growth

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Evidence for a Nuclear Role for Drosophila Dlg as a Regulator of the NURF Complex

Molecular Biology of the Cell ◽

10.1091/mbc.e21-04-0187 ◽

2021 ◽

pp. mbc.E21-04-0187

Author(s):

Katherine A. Sharp ◽

Mark J. Khoury ◽

Frederick Wirtz-Peitz ◽

David Bilder

Keyword(s):

Molecular Mechanisms ◽

Hippo Pathway ◽

Subcellular Fractionation ◽

Mass Spectrometry Data ◽

Epithelial Polarity ◽

Data Set ◽

Proximity Ligation ◽

Drosophila Wing ◽

Pathway Gene ◽

Protein Classes

Scrib, Dlg, and Lgl are basolateral regulators of epithelial polarity and tumor suppressors whose molecular mechanisms of action remain unclear. We used proximity biotinylation to identify proteins localized near Dlg in the Drosophila wing imaginal disc epithelium. In addition to expected membrane- and cytoskeleton-associated protein classes, nuclear proteins were prevalent in the resulting mass spectrometry data set, including all four members of the NURF chromatin remodeling complex. Subcellular fractionation demonstrated a nuclear pool of Dlg and proximity ligation confirmed its position near the NURF complex. Genetic analysis showed that NURF activity is also required for the overgrowth of dlg tumors, and this growth suppression correlated with a reduction in Hippo pathway gene expression. Together, these data suggest a nuclear role for Dlg in regulating chromatin and transcription through a more direct mechanism than previously thought.

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Synergistic signaling by two BMP ligands through the SAX and TKV receptors controls wing growth and patterning in Drosophila

Development ◽

10.1242/dev.125.20.3977 ◽

1998 ◽

Vol 125 (20) ◽

pp. 3977-3987 ◽

Cited By ~ 14

Author(s):

T.E. Haerry ◽

O. Khalsa ◽

M.B. O'Connor ◽

K.A. Wharton

Keyword(s):

Transcriptional Response ◽

Type I ◽

Drosophila Wing ◽

Receptor Concentration ◽

Wing Discs ◽

Response Thresholds ◽

Multiple Ligands ◽

Wing Growth ◽

Concentration Levels ◽

Signaling Activity

In Drosophila wing discs, a morphogen gradient of DPP has been proposed to determine the transcriptional response thresholds of the downstream genes sal and omb. We present evidence that the concentration of the type I receptor TKV must be low to allow long-range DPP diffusion. Low TKV receptor concentrations result, however, in low signaling activity. To enhance signaling at low DPP concentrations, we find that a second ligand, GBB, augments DPP/TKV activity. GBB signals primarily through the type I receptor SAX, which synergistically enhances TKV signaling and is required for proper OMB expression. We show that OMB expression in wing discs requires synergistic signaling by multiple ligands and receptors to overcome the limitations imposed on DPP morphogen function by receptor concentration levels.

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Genetic characterization of ebi reveals its critical role in Drosophila wing growth

Fly ◽

10.4161/fly.5.4.18276 ◽

2011 ◽

Vol 5 (4) ◽

pp. 291-303 ◽

Cited By ~ 3

Author(s):

Steven J. Marygold ◽

Cherryl Walker ◽

Mariam Orme ◽

Sally Leevers

Keyword(s):

Genetic Characterization ◽

Critical Role ◽

Drosophila Wing ◽

Wing Growth

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Control of Drosophila wing size by morphogen range and hormonal gating

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2018196117 ◽

2020 ◽

Vol 117 (50) ◽

pp. 31935-31944 ◽

Cited By ~ 1

Author(s):

Joseph Parker ◽

Gary Struhl

Keyword(s):

Cellular Response ◽

Steroid Hormone ◽

Experimental Paradigm ◽

Wing Size ◽

Larval Life ◽

Drosophila Wing ◽

The Right ◽

Wing Growth ◽

Gain Body Mass ◽

Correct Size

The stereotyped dimensions of animal bodies and their component parts result from tight constraints on growth. Yet, the mechanisms that stop growth when organs reach the right size are unknown. Growth of the Drosophila wing—a classic paradigm—is governed by two morphogens, Decapentaplegic (Dpp, a BMP) and Wingless (Wg, a Wnt). Wing growth during larval life ceases when the primordium attains full size, concomitant with the larval-to-pupal molt orchestrated by the steroid hormone ecdysone. Here, we block the molt by genetically dampening ecdysone production, creating an experimental paradigm in which the wing stops growing at the correct size while the larva continues to feed and gain body mass. Under these conditions, we show that wing growth is limited by the ranges of Dpp and Wg, and by ecdysone, which regulates the cellular response to their signaling activities. Further, we present evidence that growth terminates because of the loss of two distinct modes of morphogen action: 1) maintenance of growth within the wing proper and 2) induced growth of surrounding “pre-wing” cells and their recruitment into the wing. Our results provide a precedent for the control of organ size by morphogen range and the hormonal gating of morphogen action.

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The Hippo Pathway and YAP Signaling: Emerging Concepts in Regulation, Signaling, and Experimental Targeting Strategies With Implications for Hepatobiliary Malignancies

Gene Expression ◽

10.3727/105221619x15617324583639 ◽

2020 ◽

Vol 20 (1) ◽

pp. 67-74 ◽

Cited By ~ 1

Author(s):

Nathan Werneburg ◽

Gregory J. Gores ◽

Rory L. Smoot

Keyword(s):

Hippo Pathway ◽

Current Data ◽

Signaling Cascades ◽

Serine Threonine Kinase ◽

Feed Forward ◽

Regulatory Pathways ◽

Threonine Kinase ◽

The Hippo Pathway ◽

Hepatic Malignancies

The Hippo pathway and its effector protein YAP (a transcriptional coactivator) have been identified as important in the biology of both hepatocellular carcinoma and cholangiocarcinoma. First identified as a tumor suppressor pathway in Drosophila, the understanding of the mammalian YAP signaling and its regulation continues to expand. In its “on” function, the canonical regulatory Hippo pathway, a well-described serine/threonine kinase module, regulates YAP function by restricting its subcellular localization to the cytoplasm. In contrast, when the Hippo pathway is “off,” YAP translocates to the nucleus and drives cotranscriptional activity. Given the role of Hippo/YAP signaling in hepatic malignancies, investigators have sought to target these molecules; however, standard approaches have not been successful based on the pathways’ negative regulatory role. More recently, additional regulatory mechanisms, such as tyrosine phosphorylation, of YAP have been described. These represent positive regulatory events that may be targetable. Additionally, several groups have identified potentiating feed-forward signaling for YAP in multiple contexts, suggesting other experimental therapeutic approaches to interrupt these signaling loops. Herein we explore the current data supporting alternative YAP regulatory pathways, review the described feed-forward signaling cascades that are YAP dependent, and explore targeting strategies that have been employed in preclinical models of hepatic malignancies.

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