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Hedgehog is relayed through dynamic heparan sulfate interactions to shape its gradient

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Listed:
  • Fabian Gude

    (University of Münster)

  • Jurij Froese

    (University of Münster)

  • Dominique Manikowski

    (University of Münster)

  • Daniele Di Iorio

    (University of Münster)

  • Jean-Noël Grad

    (University of Duisburg-Essen
    Universität Stuttgart)

  • Seraphine Wegner

    (University of Münster)

  • Daniel Hoffmann

    (University of Duisburg-Essen)

  • Melissa Kennedy

    (University of Leeds
    University of Leeds
    University of Leeds
    University of Leeds)

  • Ralf P. Richter

    (University of Leeds
    University of Leeds
    University of Leeds
    University of Leeds)

  • Georg Steffes

    (University of Münster)

  • Kay Grobe

    (University of Münster)

Abstract

Cellular differentiation is directly determined by concentration gradients of morphogens. As a central model for gradient formation during development, Hedgehog (Hh) morphogens spread away from their source to direct growth and pattern formation in Drosophila wing and eye discs. What is not known is how extracellular Hh spread is achieved and how it translates into precise gradients. Here we show that two separate binding areas located on opposite sides of the Hh molecule can interact directly and simultaneously with two heparan sulfate (HS) chains to temporarily cross-link the chains. Mutated Hh lacking one fully functional binding site still binds HS but shows reduced HS cross-linking. This, in turn, impairs Hhs ability to switch between both chains in vitro and results in striking Hh gradient hypomorphs in vivo. The speed and propensity of direct Hh switching between HS therefore shapes the Hh gradient, revealing a scalable design principle in morphogen-patterned tissues.

Suggested Citation

  • Fabian Gude & Jurij Froese & Dominique Manikowski & Daniele Di Iorio & Jean-Noël Grad & Seraphine Wegner & Daniel Hoffmann & Melissa Kennedy & Ralf P. Richter & Georg Steffes & Kay Grobe, 2023. "Hedgehog is relayed through dynamic heparan sulfate interactions to shape its gradient," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36450-y
    DOI: 10.1038/s41467-023-36450-y
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    References listed on IDEAS

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    1. Timothy A. Sanders & Esther Llagostera & Maria Barna, 2013. "Specialized filopodia direct long-range transport of SHH during vertebrate tissue patterning," Nature, Nature, vol. 497(7451), pages 628-632, May.
    2. Ana-Citlali Gradilla & Esperanza González & Irene Seijo & German Andrés & Marcus Bischoff & Laura González-Mendez & Vanessa Sánchez & Ainhoa Callejo & Carmen Ibáñez & Milagros Guerra & João Ramalho Or, 2014. "Exosomes as Hedgehog carriers in cytoneme-mediated transport and secretion," Nature Communications, Nature, vol. 5(1), pages 1-13, December.
    3. Yohanns Bellaiche & Inge The & Norbert Perrimon, 1998. "Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion," Nature, Nature, vol. 394(6688), pages 85-88, July.
    4. Shuizi Rachel Yu & Markus Burkhardt & Matthias Nowak & Jonas Ries & Zdeněk Petrášek & Steffen Scholpp & Petra Schwille & Michael Brand, 2009. "Fgf8 morphogen gradient forms by a source-sink mechanism with freely diffusing molecules," Nature, Nature, vol. 461(7263), pages 533-536, September.
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