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

Fabian Gude, Jurij Froese, Dominique Manikowski, Daniele Di Iorio, Jean-Noël Grad, Seraphine Wegner, Daniel Hoffmann, Melissa Kennedy, Ralf P. Richter, Georg Steffes () and Kay Grobe ()
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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
Seraphine Wegner: University of Münster
Daniel Hoffmann: University of Duisburg-Essen
Melissa Kennedy: University of Leeds
Ralf P. Richter: University of Leeds
Georg Steffes: University of Münster
Kay Grobe: University of Münster

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36450-y

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