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Related Experiment Video

Updated: Nov 12, 2025

Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development
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Simultaneous binding of Guidance Cues NET1 and RGM blocks extracellular NEO1 signaling.

Ross A Robinson1, Samuel C Griffiths1, Lieke L van de Haar2

  • 1Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.

Cell
|March 19, 2021
PubMed
Summary

Neogenin (NEO1) integrates opposing signals from Netrin-1 (NET1) and repulsive guidance molecule (RGM) ligands by forming a ternary complex. This super-assembly silences downstream signaling, preventing cell growth cone collapse and regulating neuron migration.

Keywords:
NeogeninNetrinaxon regenerationcell migrationcell surface receptorscomplex structuremorphogen signalingprotein-protein interactionsrepulsive guidance moleculesignal transduction

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Area of Science:

  • Molecular Biology
  • Neuroscience
  • Cell Biology

Background:

  • Cell surface receptors integrate diverse extracellular signals during crucial processes like migration and differentiation.
  • Neogenin (NEO1) exhibits dual functionality, mediating attraction via Netrin-1 (NET1) and repulsion via repulsive guidance molecule (RGM) ligands.

Purpose of the Study:

  • To elucidate the mechanism of signal integration when NEO1 simultaneously binds to ligands with opposing functions.
  • To determine the structural basis for how NEO1 reconciles attractive and repulsive cues.

Main Methods:

  • X-ray crystallography to determine the structure of the NEO1-NET1-RGM complex.
  • Biochemical assays to assess downstream signaling.
  • Cell-based assays to evaluate growth cone collapse and neuron migration.

Main Results:

  • A ternary complex of NEO1, NET1, and RGM forms, creating a "trimer-of-trimers" super-assembly at the cell membrane.
  • This super-assembly inhibits RGMA-NEO1-mediated growth cone collapse and RGMA/NET1-NEO1-mediated neuron migration.
  • Formation of signaling-competent complexes and NEO1 ectodomain clustering are prevented by the super-assembly.

Conclusions:

  • Simultaneous ligand binding to a single receptor does not always result in competitive signaling.
  • A higher-order super-complex formation can lead to the reciprocal silencing of opposing functional outputs.
  • This mechanism provides insight into how cells integrate complex extracellular cues for precise cellular responses.