Notch receptor-ligand binding facilitates extracellular vesicle-mediated neuron-to-neuron communication

Yi Zhi Wang, Charlotte C.M. Castillon, Kamil K. Gebis, Elizabeth T. Bartom, Alessandra d'Azzo, Anis Contractor, Jeffrey N. Savas*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Extracellular vesicles (EVs) facilitate intercellular communication by transferring cargo between cells in a variety of tissues. However, how EVs achieve cell-type-specific intercellular communication is still largely unknown. We found that Notch1 and Notch2 proteins are expressed on the surface of neuronal EVs that have been generated in response to neuronal excitatory synaptic activity. Notch ligands bind these EVs on the neuronal plasma membrane, trigger their internalization, activate the Notch signaling pathway, and drive the expression of Notch target genes. The generation of these neuronal EVs requires the endosomal sorting complex required for transport-associated protein Alix. Adult Alix conditional knockout mice have reduced hippocampal Notch signaling activation and glutamatergic synaptic protein expression. Thus, EVs facilitate neuron-to-neuron communication via the Notch receptor-ligand system in the brain.

Original languageEnglish (US)
Article number113680
JournalCell reports
Volume43
Issue number2
DOIs
StatePublished - Feb 27 2024

Funding

Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center . This research was supported in part through the computational resources and staff contributions provided for the Quest high-performance computing facility at Northwestern University , which is jointly supported by the Office of the Provost , the Office for Research, and Northwestern University Information Technology. We would like to thank Dr. Rémy Sadoul and Dr. Frank Kirchhoff for sharing Alix fl/fl mice with us, Dr. Vincent C. Luca for sharing the Delta MAX plasmids, Dr. Ali Shilatifard, Dr. Fei Chen, and Stacy A. Marshall for helping with RNA sequencing, Dr. Farida Vadimovn a Korobova and Lennell Reynolds Jr for their help with imaging, Dr. Jian Xu and Dr. Toshihiro Nomura for help of vibratome sectioning of mouse hippocampal slices, and Samuel N. Smukowski and David R. Graykowski for technical support. This work was supported by an Individual Biomedical Research Award from The Hartwell Foundation and R01 AG061787 to J.N.S., R01 MH099114 to A.C., and R50 CA221848 to E.T.B., NIH grants AR049867 , CA021765 , the Assisi Foundation of Memphis , and the American Lebanese Syrian Associated Charities (ALSAC) of SJCRH to A.d’A. A.d’A holds an endowed chair in Genetics and Gene Therapy from the Jewelry Charity Fund. A provisional patent application has been submitted through NU INVO regarding the use of Notch EVs for cell-type-specific cargo delivery.

Keywords

  • Alix
  • CP: Neuroscience
  • Notch
  • excitatory synaptic activity
  • extracellular vesicles
  • glutamatergic synapse
  • neuron communication

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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