Publications by category
Journal articles
Gardilla AC, Sanchez D, Brunt L, Scholpp S (In Press). From top to bottom: Cell polarity in Hedgehog and Wnt trafficking. BMC Biology
Brunt L, Greicius G, Evans BD, Virshup DM, Wedgwood KCA, Scholpp S (In Press). Vangl2 regulates the dynamics of Wnt cytonemes in vertebrates.
Abstract:
Vangl2 regulates the dynamics of Wnt cytonemes in vertebrates
AbstractThe Wnt signalling network regulates cell proliferation and cell differentiation as well as migration and polarity in development of multicellular organisms. However, it is still unclear how distribution of Wnt ligands is precisely controlled to fulfil all of these different functions. Here, we show that the four-pass transmembrane protein Vangl2 occupies a central role in determining the distribution of Wnt by cytonemes in vertebrate tissue. In zebrafish epiblast cells, mouse intestinal telocytes and human gastric cancer cells, activation of Vangl2 leads to the generation of fewer but extremely long cytonemes, which start to branch and deliver Wnt protein to multiple cells. The Vangl2-activated cytonemes increase Wnt/β-catenin signalling in the surrounding cells. Concordantly, inhibition of Vangl2 function leads to the formation of shorter cytonemes and reduced paracrine Wnt/β-catenin signal activation. A mathematical model simulating the observed Vangl2 functions on cytonemes in zebrafish gastrulation predicts an anterior shift of the morphogenetic signalling gradient, altered tissue patterning, and a loss of the sharpness of tissue domains. We confirmed these predictions during anteroposterior patterning in the zebrafish neural plate. In summary, we show that Vangl2 - a core member of the PCP signalling component - is fundamental to paracrine Wnt/β-catenin signalling by controlling cytoneme behaviour in vertebrate development and tissue homeostasis.
Abstract.
Brunt L, Greicius G, Rogers S, Evans BD, Virshup DM, Wedgwood KCA, Scholpp S (2021). Vangl2 promotes the formation of long cytonemes to enable distant Wnt/β-catenin signaling.
Nat Commun,
12(1).
Abstract:
Vangl2 promotes the formation of long cytonemes to enable distant Wnt/β-catenin signaling.
Wnt signaling regulates cell proliferation and cell differentiation as well as migration and polarity during development. However, it is still unclear how the Wnt ligand distribution is precisely controlled to fulfil these functions. Here, we show that the planar cell polarity protein Vangl2 regulates the distribution of Wnt by cytonemes. In zebrafish epiblast cells, mouse intestinal telocytes and human gastric cancer cells, Vangl2 activation generates extremely long cytonemes, which branch and deliver Wnt protein to multiple cells. The Vangl2-activated cytonemes increase Wnt/β-catenin signaling in the surrounding cells. Concordantly, Vangl2 inhibition causes fewer and shorter cytonemes to be formed and reduces paracrine Wnt/β-catenin signaling. A mathematical model simulating these Vangl2 functions on cytonemes in zebrafish gastrulation predicts a shift of the signaling gradient, altered tissue patterning, and a loss of tissue domain sharpness. We confirmed these predictions during anteroposterior patterning in the zebrafish neural plate. In summary, we demonstrate that Vangl2 is fundamental to paracrine Wnt/β-catenin signaling by controlling cytoneme behaviour.
Abstract.
Author URL.
Brunt L, Scholpp S (2018). The function of endocytosis in Wnt signaling.
Cellular and Molecular Life Sciences,
75(5), 785-795.
Abstract:
The function of endocytosis in Wnt signaling
Wnt growth factors regulate one of the most important signaling networks during development, tissue homeostasis and disease. Despite the biological importance of Wnt signaling, the mechanism of endocytosis during this process is ill described. Wnt molecules can act as paracrine signals, which are secreted from the producing cells and transported through neighboring tissue to activate signaling in target cells. Endocytosis of the ligand is important at several stages of action: One central function of endocytic trafficking in the Wnt pathway occurs in the source cell. Furthermore, the β-catenin-dependent Wnt ligands require endocytosis for signal activation and to regulate gene transcription in the responding cells. Alternatively, Wnt/β-catenin-independent signaling regulates endocytosis of cell adherence plaques to control cell migration. In this comparative review, we elucidate these three fundamental interconnected functions, which together regulate cellular fate and cellular behavior. Based on established hypotheses and recent findings, we develop a revised picture for the complex function of endocytosis in the Wnt signaling network.
Abstract.
Brunt LH, Begg K, Kague E, Cross S, Hammond CL (2017). Wnt signalling controls the response to mechanical loading during Zebrafish joint development.
DevelopmentAbstract:
Wnt signalling controls the response to mechanical loading during Zebrafish joint development
Joint morphogenesis requires mechanical activity during development. Loss of mechanical strain causes abnormal joint development, which can impact long term joint health. While cell orientation and proliferation are known to shape the joint, dynamic imaging of developing joints in vivo has not been possible in other species. Using genetic labelling techniques in zebrafish we were able, for the first time, to dynamically track cell behaviours in intact moving joints. We identify that proliferation and migration, which contribute to joint morphogenesis, are mechanically controlled and are significantly reduced in immobilised larvae. By comparison to strain maps of the developing skeleton we identify canonical Wnt signalling as a candidate to transduce mechanical forces into joint cell behaviours. We show that in the jaw Wnt signalling is reduced specifically in regions of high strain in response to loss of muscle activity. By pharmacological manipulation of canonical Wnt signalling we demonstrate that Wnt acts downstream of mechanical activity and is required for joint patterning and chondrocyte maturation. Wnt16, also downstream of muscle activity, controls proliferation and migration, but plays no role in chondrocyte intercalation.
Abstract.
Brunt LH, Roddy KA, Rayfield EJ, Hammond CL (2016). Building Finite Element Models to Investigate Zebrafish Jaw Biomechanics. Journal of Visualized Experiments(118).
Brunt LH, Skinner REH, Roddy KA, Araujo NM, Rayfield EJ, Hammond CL (2016). Differential effects of altered patterns of movement and strain on joint cell behaviour and skeletal morphogenesis. Osteoarthritis and Cartilage, 24(11), 1940-1950.
Brunt LH, Norton JL, Bright JA, Rayfield EJ, Hammond CL (2015). Finite element modelling predicts changes in joint shape and cell behaviour due to loss of muscle strain in jaw development. Journal of Biomechanics, 48(12), 3112-3122.
Mitchell RE, Huitema LFA, Skinner REH, Brunt LH, Severn C, Schulte-Merker S, Hammond CL (2013). New tools for studying osteoarthritis genetics in zebrafish. Osteoarthritis and Cartilage, 21(2), 269-278.
Publications by year
In Press
Gardilla AC, Sanchez D, Brunt L, Scholpp S (In Press). From top to bottom: Cell polarity in Hedgehog and Wnt trafficking. BMC Biology
Brunt L, Greicius G, Evans BD, Virshup DM, Wedgwood KCA, Scholpp S (In Press). Vangl2 regulates the dynamics of Wnt cytonemes in vertebrates.
Abstract:
Vangl2 regulates the dynamics of Wnt cytonemes in vertebrates
AbstractThe Wnt signalling network regulates cell proliferation and cell differentiation as well as migration and polarity in development of multicellular organisms. However, it is still unclear how distribution of Wnt ligands is precisely controlled to fulfil all of these different functions. Here, we show that the four-pass transmembrane protein Vangl2 occupies a central role in determining the distribution of Wnt by cytonemes in vertebrate tissue. In zebrafish epiblast cells, mouse intestinal telocytes and human gastric cancer cells, activation of Vangl2 leads to the generation of fewer but extremely long cytonemes, which start to branch and deliver Wnt protein to multiple cells. The Vangl2-activated cytonemes increase Wnt/β-catenin signalling in the surrounding cells. Concordantly, inhibition of Vangl2 function leads to the formation of shorter cytonemes and reduced paracrine Wnt/β-catenin signal activation. A mathematical model simulating the observed Vangl2 functions on cytonemes in zebrafish gastrulation predicts an anterior shift of the morphogenetic signalling gradient, altered tissue patterning, and a loss of the sharpness of tissue domains. We confirmed these predictions during anteroposterior patterning in the zebrafish neural plate. In summary, we show that Vangl2 - a core member of the PCP signalling component - is fundamental to paracrine Wnt/β-catenin signalling by controlling cytoneme behaviour in vertebrate development and tissue homeostasis.
Abstract.
2022
Zhang C, Brunt L, Rogers S, Scholpp S (2022). Cytoneme-mediated transport of active Wnt5b/Ror2 complexes in zebrafish gastrulation.
2021
Brunt L, Greicius G, Rogers S, Evans BD, Virshup DM, Wedgwood KCA, Scholpp S (2021). Vangl2 promotes the formation of long cytonemes to enable distant Wnt/β-catenin signaling.
Nat Commun,
12(1).
Abstract:
Vangl2 promotes the formation of long cytonemes to enable distant Wnt/β-catenin signaling.
Wnt signaling regulates cell proliferation and cell differentiation as well as migration and polarity during development. However, it is still unclear how the Wnt ligand distribution is precisely controlled to fulfil these functions. Here, we show that the planar cell polarity protein Vangl2 regulates the distribution of Wnt by cytonemes. In zebrafish epiblast cells, mouse intestinal telocytes and human gastric cancer cells, Vangl2 activation generates extremely long cytonemes, which branch and deliver Wnt protein to multiple cells. The Vangl2-activated cytonemes increase Wnt/β-catenin signaling in the surrounding cells. Concordantly, Vangl2 inhibition causes fewer and shorter cytonemes to be formed and reduces paracrine Wnt/β-catenin signaling. A mathematical model simulating these Vangl2 functions on cytonemes in zebrafish gastrulation predicts a shift of the signaling gradient, altered tissue patterning, and a loss of tissue domain sharpness. We confirmed these predictions during anteroposterior patterning in the zebrafish neural plate. In summary, we demonstrate that Vangl2 is fundamental to paracrine Wnt/β-catenin signaling by controlling cytoneme behaviour.
Abstract.
Author URL.
2018
Brunt L, Scholpp S (2018). The function of endocytosis in Wnt signaling.
Cellular and Molecular Life Sciences,
75(5), 785-795.
Abstract:
The function of endocytosis in Wnt signaling
Wnt growth factors regulate one of the most important signaling networks during development, tissue homeostasis and disease. Despite the biological importance of Wnt signaling, the mechanism of endocytosis during this process is ill described. Wnt molecules can act as paracrine signals, which are secreted from the producing cells and transported through neighboring tissue to activate signaling in target cells. Endocytosis of the ligand is important at several stages of action: One central function of endocytic trafficking in the Wnt pathway occurs in the source cell. Furthermore, the β-catenin-dependent Wnt ligands require endocytosis for signal activation and to regulate gene transcription in the responding cells. Alternatively, Wnt/β-catenin-independent signaling regulates endocytosis of cell adherence plaques to control cell migration. In this comparative review, we elucidate these three fundamental interconnected functions, which together regulate cellular fate and cellular behavior. Based on established hypotheses and recent findings, we develop a revised picture for the complex function of endocytosis in the Wnt signaling network.
Abstract.
2017
Brunt LH, Begg K, Kague E, Cross S, Hammond CL (2017). Wnt signalling controls the response to mechanical loading during Zebrafish joint development.
DevelopmentAbstract:
Wnt signalling controls the response to mechanical loading during Zebrafish joint development
Joint morphogenesis requires mechanical activity during development. Loss of mechanical strain causes abnormal joint development, which can impact long term joint health. While cell orientation and proliferation are known to shape the joint, dynamic imaging of developing joints in vivo has not been possible in other species. Using genetic labelling techniques in zebrafish we were able, for the first time, to dynamically track cell behaviours in intact moving joints. We identify that proliferation and migration, which contribute to joint morphogenesis, are mechanically controlled and are significantly reduced in immobilised larvae. By comparison to strain maps of the developing skeleton we identify canonical Wnt signalling as a candidate to transduce mechanical forces into joint cell behaviours. We show that in the jaw Wnt signalling is reduced specifically in regions of high strain in response to loss of muscle activity. By pharmacological manipulation of canonical Wnt signalling we demonstrate that Wnt acts downstream of mechanical activity and is required for joint patterning and chondrocyte maturation. Wnt16, also downstream of muscle activity, controls proliferation and migration, but plays no role in chondrocyte intercalation.
Abstract.
2016
Brunt LH, Roddy KA, Rayfield EJ, Hammond CL (2016). Building Finite Element Models to Investigate Zebrafish Jaw Biomechanics. Journal of Visualized Experiments(118).
Brunt LH, Skinner REH, Roddy KA, Araujo NM, Rayfield EJ, Hammond CL (2016). Differential effects of altered patterns of movement and strain on joint cell behaviour and skeletal morphogenesis. Osteoarthritis and Cartilage, 24(11), 1940-1950.
2015
Brunt LH, Norton JL, Bright JA, Rayfield EJ, Hammond CL (2015). Finite element modelling predicts changes in joint shape and cell behaviour due to loss of muscle strain in jaw development. Journal of Biomechanics, 48(12), 3112-3122.
2013
Mitchell RE, Huitema LFA, Skinner REH, Brunt LH, Severn C, Schulte-Merker S, Hammond CL (2013). New tools for studying osteoarthritis genetics in zebrafish. Osteoarthritis and Cartilage, 21(2), 269-278.