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Pleiotrophin regulates presynaptic assembly and function through heparan sulfate-dependent binding to neurexin1.

Overview

Authors: Qin Xu1, Andrew W. Schilling2, Alexander W. Sorum2, Peipei Zhang1, Destini C. Weller1, Donovan Whitfield1, Gokul Velayoudame1, Allison J. Wu1, Qian Sun1, Linda C. Hsieh-Wilson2, Peng Zhang1,3
ORCID iDs: Andrew W. Schilling
  1. Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
  2. Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, CA 91125, USA
  3. Lead contact
Institutions: Case Western Reserve University (United States); California Institute of Technology (United States)
Journal: Cell reports, volume 45, issue 8, article 117827
Dates: published online 12 August 2026; in print August 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1016/j.celrep.2026.117827 · PMID 42585021 · PMCID PMC13587102 · OpenAlex W7202257901
Open access: gold, a free copy (OpenAlex)
Status: code on request
Categories: cellular / molecular (subfield)
Methods: Spectral & time-frequency, Statistics
Keywords: Extracellular matrix, proteoglycan, Presynaptic Assembly, Synaptic Organizer, Cp: Molecular Biology, Cp: Neuroscience, Extracellular Glycan
Topic: Proteoglycans and glycosaminoglycans research (Cell Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: NIMH NIH HHS (R01 MH130476); Simons Foundation (AN-AR-Independence Faculty-00606479); National Institutes of Health (2R01AG087519-09); National Institute of Mental Health (1R01MH130476); NIA NIH HHS (R01 AG087519)
Citations: not cited yet (Europe PMC); 52 references in the paper
Research resources: Rabbit anti-GPC4 RRID:AB_10640157, Rabbit anti-Nrxn1 RRID:AB_10697816, Rabbit anti-PTPσ RRID:AB_10858319, Mouse anti-HS stub (3G10) RRID:AB_10892311, Rabbit anti-pan-Nrxn RRID:AB_10917110, Rabbit anti-vGlut1 RRID:AB_2301751, Rabbit anti-β Actin RRID:AB_2305186, Anti-Synapsin1 RRID:AB_2619772, Chicken anti-MAP2 RRID:AB_2619881, Anti-RIM RRID:AB_2631216, Mouse anti-V5 RRID:AB_2792973, Rabbit anti-Ptn RRID:AB_2806790, Mouse anti-PSD95 RRID:AB_2877189, HS20 (anti-HS) RRID:AB_3696136

Abstract

Synapses are the fundamental units of neural circuits, and their dysfunction contributes to numerous neuropsychiatric disorders. Although synaptic adhesion proteins have been well studied, how extracellular cues and matrix glycans specify synaptic properties remains much less well understood. Here, we identify pleiotrophin (Ptn) as a regulator of presynaptic development. Affinity purification-based proteomics shows that Ptn associates with heparan sulfate (HS)-modified neurexin1 (HS-Nrxn1) in the brain through an HS-glycan-dependent mechanism. Glycan microarray analyses further reveal that Ptn selectively recognizes defined HS sulfation motifs. Functionally, Ptn requires both HS glycans and Nrxns to induce presynaptic assembly in cultured neurons. In vivo, Ptn deletion disrupts presynaptic protein clustering, reduces neurotransmitter release probability at CA3-CA1 synapses, and impairs contextual fear discrimination. Together, these findings establish Ptn as an extracellular organizer of presynaptic development and support a model in which Nrxn1’s HS glycan provides a platform for extracellular ligand recruitment.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

The paper's code and data availability statement is in the Data section.

Tracing map

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Data

No dataset and no data link were found in the paper.

Data and code availability

Data: The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE45 partner repository and are publicly available under accession number PXD081065. The accession number is also listed in the key resources table.

Code: This paper does not report original code.

All other items: Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 3, 28 September 2026

  • Publisher: n/a → Cell Press

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 11 authors, 7 keywords, 5 funders, 52 references, 14 RRIDs.

Cite

This paper

Xu, Q., Schilling, A. W., Sorum, A. W., Zhang, P., Weller, D. C., Whitfield, D., Velayoudame, G., Wu, A. J., Sun, Q., Hsieh-Wilson, L. C., & Zhang, P. (2026). Pleiotrophin regulates presynaptic assembly and function through heparan sulfate-dependent binding to neurexin1. Cell reports, 45(8), 117827. https://doi.org/10.1016/j.celrep.2026.117827

BibTeX

@article{xu2026pleiotrophin,
author = {Xu, Qin and Schilling, Andrew W. and Sorum, Alexander W. and Zhang, Peipei and Weller, Destini C. and Whitfield, Donovan and Velayoudame, Gokul and Wu, Allison J. and Sun, Qian and Hsieh-Wilson, Linda C. and Zhang, Peng},
title = {{Pleiotrophin regulates presynaptic assembly and function through heparan sulfate-dependent binding to neurexin1}},
journal = {Cell reports},
year = {2026},
month = aug,
volume = {45},
number = {8},
pages = {117827},
publisher = {Cell Press},
issn = {2211-1247},
doi = {10.1016/j.celrep.2026.117827},
url = {https://doi.org/10.1016/j.celrep.2026.117827},
pmid = {42585021},
pmcid = {PMC13587102}
}

RIS

TY - JOUR
AU - Xu, Qin
AU - Schilling, Andrew W.
AU - Sorum, Alexander W.
AU - Zhang, Peipei
AU - Weller, Destini C.
AU - Whitfield, Donovan
AU - Velayoudame, Gokul
AU - Wu, Allison J.
AU - Sun, Qian
AU - Hsieh-Wilson, Linda C.
AU - Zhang, Peng
TI - Pleiotrophin regulates presynaptic assembly and function through heparan sulfate-dependent binding to neurexin1
T2 - Cell reports
J2 - Cell Rep
PY - 2026
DA - 2026/08/12
VL - 45
IS - 8
SP - 117827
SN - 2211-1247
PB - Cell Press
DO - 10.1016/j.celrep.2026.117827
UR - https://doi.org/10.1016/j.celrep.2026.117827
LA - en
ER -

CSL-JSON

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