RTN4/NoGo-receptor binding to BAI adhesion-GPCRs regulates neuronal development

Cell. 2021 Nov 24;184(24):5869-5885.e25. doi: 10.1016/j.cell.2021.10.016. Epub 2021 Nov 9.


RTN4-binding proteins were widely studied as "NoGo" receptors, but their physiological interactors and roles remain elusive. Similarly, BAI adhesion-GPCRs were associated with numerous activities, but their ligands and functions remain unclear. Using unbiased approaches, we observed an unexpected convergence: RTN4 receptors are high-affinity ligands for BAI adhesion-GPCRs. A single thrombospondin type 1-repeat (TSR) domain of BAIs binds to the leucine-rich repeat domain of all three RTN4-receptor isoforms with nanomolar affinity. In the 1.65 Å crystal structure of the BAI1/RTN4-receptor complex, C-mannosylation of tryptophan and O-fucosylation of threonine in the BAI TSR-domains creates a RTN4-receptor/BAI interface shaped by unusual glycoconjugates that enables high-affinity interactions. In human neurons, RTN4 receptors regulate dendritic arborization, axonal elongation, and synapse formation by differential binding to glial versus neuronal BAIs, thereby controlling neural network activity. Thus, BAI binding to RTN4/NoGo receptors represents a receptor-ligand axis that, enabled by rare post-translational modifications, controls development of synaptic circuits.

Keywords: BAI; C-mannosylation; NoGo receptor; O-fucosylation; RTN4R; adhesion-GPCR; human neuron; morphology; neuronal network activity; synapse formation; synaptic transmission.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adipokines / metabolism
  • Amino Acid Sequence
  • Angiogenesis Inhibitors / metabolism*
  • Animals
  • Axons / metabolism
  • Brain / metabolism*
  • Cell Adhesion
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Complement C1q / metabolism
  • Dendrites / metabolism
  • Glycosylation
  • HEK293 Cells
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Ligands
  • Mice, Inbred C57BL
  • Nerve Net / metabolism
  • Neurogenesis*
  • Neurons / metabolism*
  • Nogo Proteins / metabolism*
  • Nogo Receptors / metabolism*
  • Polysaccharides / metabolism
  • Protein Binding
  • Protein Domains
  • Receptors, G-Protein-Coupled / metabolism*
  • Sequence Deletion
  • Synapses / metabolism
  • Synaptic Transmission / physiology


  • Adipokines
  • Angiogenesis Inhibitors
  • C1QL3 protein, human
  • Cell Adhesion Molecules, Neuronal
  • Ligands
  • Nogo Proteins
  • Nogo Receptors
  • Polysaccharides
  • RTN4 protein, human
  • Receptors, G-Protein-Coupled
  • neuroligin 1
  • Complement C1q