Cell
Volume 174, Issue 6, 6 September 2018, Pages 1450-1464.e23
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Article
Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships

https://doi.org/10.1016/j.cell.2018.07.002Get rights and content
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Highlights

  • Brain central synaptic organizers neurexins are heparan sulfate (HS) proteoglycans

  • A dual HS and protein domain mode mediates neurexin binding to neuroligin and LRRTM

  • HS increases neurexin heterogeneity and expands its interactome to HS binding factors

  • HS glycan on neurexin is required for normal synaptic development and mouse survival

Summary

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.

Keywords

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

Cited by (0)

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Present address: Kleysen Institute for Advanced Medicine and Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R3E 0Z3, Canada

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Present address: The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China

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These authors contributed equally

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