Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships

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...

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Bibliographic Details
Published in:Cell Vol. 174; no. 6; p. 1450
Main Authors: Zhang, Peng, Lu, Hong, Peixoto, Rui T, Pines, Mary K, Ge, Yuan, Oku, Shinichiro, Siddiqui, Tabrez J, Xie, Yicheng, Wu, Wenlan, Archer-Hartmann, Stephanie, Yoshida, Keitaro, Tanaka, Kenji F, Aricescu, A Radu, Azadi, Parastoo, Gordon, Michael D, Sabatini, Bernardo L, Wong, Rachel O L, Craig, Ann Marie
Format: Journal Article
Language:English
Published: United States 06.09.2018
Subjects:
Amino Acid Sequence
Animals
Calcium-Binding Proteins
Cell Adhesion Molecules, Neuronal - antagonists & inhibitors
Cell Adhesion Molecules, Neuronal - genetics
Cell Adhesion Molecules, Neuronal - metabolism
Drosophila
Drosophila Proteins - antagonists & inhibitors
Drosophila Proteins - genetics
Drosophila Proteins - metabolism
Female
Glycopeptides - analysis
Heparitin Sulfate - chemistry
Heparitin Sulfate - metabolism
Humans
Membrane Proteins
Mice
Mice, Inbred C57BL
Nerve Tissue Proteins
Neural Cell Adhesion Molecules - antagonists & inhibitors
Neural Cell Adhesion Molecules - genetics
Neural Cell Adhesion Molecules - metabolism
Neurons - cytology
Neurons - metabolism
Protein Binding
Rats
RNA Interference
RNA, Small Interfering - metabolism
Sequence Alignment
Synapses - metabolism
LRRTM
heparan sulphate
synaptic transmission
thorny excrescence
mossy fiber
synaptogenesis
neurexin
neuroligin
proteoglycan
synaptic adhesion protein
ISSN:1097-4172, 1097-4172
Online Access:Get more information
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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.
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2018.07.002