Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships

Peng Zhang, Hong Lu, Rui T. Peixoto, Mary K. Pines, Yuan Ge, Shinichiro Oku, Tabrez J. Siddiqui, Yicheng Xie, Wenlan Wu, Stephanie Archer-Hartmann, Keitaro Yoshida, Kenji F. Tanaka, A. Radu Aricescu, Parastoo Azadi, Michael D. Gordon, Bernardo L. Sabatini, Rachel O.L. Wong, Ann Marie Craig

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Synapses are fundamental units of communication in the brain. The prototypical synapse-organizing complex neurexin-neuroligin mediates synapse development and function and is central to a shared genetic risk pathway in autism and schizophrenia. Neurexin's role in synapse development is thought to be mediated purely by its protein domains, but we reveal a requirement for a rare glycan modification. Mice lacking heparan sulfate (HS) on neurexin-1 show reduced survival, as well as structural and functional deficits at central synapses. HS directly binds postsynaptic partners neuroligins and LRRTMs, revealing a dual binding mode involving intrinsic glycan and protein domains for canonical synapse-organizing complexes. Neurexin HS chains also bind novel ligands, potentially expanding the neurexin interactome to hundreds of HS-binding proteins. Because HS structure is heterogeneous, our findings indicate an additional dimension to neurexin diversity, provide a molecular basis for fine-tuning synaptic function, and open therapeutic directions targeting glycan-binding motifs critical for brain development. Neurexins, major synaptic-organizing proteins, are heparan sulfate (HS) proteoglycans, and HS modification is required for neurexin functions in synaptic transmission, development, and behavior.

Original languageEnglish
Pages (from-to)1450-1464.e23
JournalCell
Volume174
Issue number6
DOIs
Publication statusPublished - 2018 Sep 6

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Keywords

  • LRRTM
  • heparan sulphate
  • mossy fiber
  • neurexin
  • neuroligin
  • proteoglycan
  • synaptic adhesion protein
  • synaptic transmission
  • synaptogenesis
  • thorny excrescence

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zhang, P., Lu, H., Peixoto, R. T., Pines, M. K., Ge, Y., Oku, S., Siddiqui, T. J., Xie, Y., Wu, W., Archer-Hartmann, S., Yoshida, K., Tanaka, K. F., Aricescu, A. R., Azadi, P., Gordon, M. D., Sabatini, B. L., Wong, R. O. L., & Craig, A. M. (2018). Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships. Cell, 174(6), 1450-1464.e23. https://doi.org/10.1016/j.cell.2018.07.002