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Delayed astrocyte development impairs Sema6a-Plxna2/4-mediated astrocyte-neuron crosstalk and causes depressive-like behavior.

Overview

Authors: Xin Jiang1, Yanqing Qi1, Lin Yang1,2, Feihong Yang1, Rongliang Guo1,3, Liang Li1, Kun Wang1, Lichen Sun4, Dan Dai5, Hanchen Liu5, Yanjing Gao1, Mengge Sun1, Xiaolei Song1, Zhuangzhi Zhang1, Zhejun Xu1, Bin Luo6, Yunli Xie1, Zhengang Yang1, Miao He1, Dashi Qi4, Xiaodan Zhang1,7, Guoping Liu1,5,8
ORCID iDs: Hanchen Liu, Zhuangzhi Zhang, Zhejun Xu, Bin Luo, Yunli Xie, Zhengang Yang, Miao He, Dashi Qi, Xiaodan Zhang, Guoping Liu
  1. State Key Laboratory of Brain Function and Disorders, Ministry of Education Frontiers Center for Brain Science, Institutes of Brain Science, Department of Rehabilitation, Huashan Hospital, Fudan University,Shanghai, China
  2. Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine,New Haven, CT USA
  3. Department of Central Laboratory, Affiliated Hospital of Hebei University of Engineering,Handan Hebei, China
  4. Center for Clinical Research and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji University,Shanghai, P.R. China
  5. Neurovascular Center, Changhai Hospital, Institute of Neuroscience, Key Laboratory of Molecular Neurobiology, NMU,Shanghai, China
  6. Chinese Institutes for Medical Research (CIMR), Beijing, China
  7. Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Lab of Reproduction and Development, Shanghai Key Lab of Female Reproductive Endocrine Related Diseases,Shanghai, China
  8. State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China
Institutions: Fudan University (China); Yale University (United States); Affiliated Hospital of Hebei University (China); Tongji University (China); Changhai Hospital (China); Obstetrics and Gynecology Hospital of Fudan University (China)
Journal: Nature communications, volume 17, issue 1, article 8800
Dates: received 12 December 2024; accepted 7 July 2026; published online 18 July 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41467-026-75697-z · PMID 42471335 · PMCID PMC13494039 · OpenAlex W7169648325
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: mouse (organism), depression (population)
Methods: Spectral & time-frequency, Statistics, Smoothing, state filtering, decompositions, Evoked potentials
Keywords: Gliogenesis, Glial development
MeSH: Astrocytes*, Depression*, Neurons*, Receptors, Cell Surface*, Semaphorins*, Animals, Behavior, Animal, Cell Communication, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Tissue Proteins, Neurodevelopment, Signal Transduction (* major topic)
Topic: Neurogenesis and neuroplasticity mechanisms (Developmental Neuroscience, Neuroscience), according to OpenAlex
Funding: National Science Foundation of China | National Natural Science Foundation of China-Yunnan Joint Fund (NSFC-Yunnan Joint Fund) (3210070481, 82501953, 31820103006, 82271197, 81974175)
Citations: not cited yet (Europe PMC); 111 references in the paper

Abstract

Neural functions and circuit formation rely on intricate crosstalk among various cell types during critical periods. Disruptions or delays in this crosstalk between neurons and astrocytes lead to abnormal neural functions and neurodevelopmental disorders. However, the lack of robust mouse models to study the crosstalk between astrocytes and neurons thus renders unclear the implications of impeding such interactions. In this study, we demonstrate that Egfr knockout during the critical period of neuronal maturation results in a transient absence of astrocytes, with recovery observed in adult mice. This model thus provides a unique opportunity to investigate the effects of impaired astrocyte-neuron communication during development. Mechanically, we show that loss of Egfr disrupts the Egfr-pERK-Epb41l2 signaling axis, which in turn prevents glial progenitor cells from migrating outward. More importantly, Egfr deficiency during the critical period compromises astrocyte-neuron communication via the Sema6a-Plxna2/4 ligand-receptor pair. This impaired intercellular crosstalk reduces neuronal dendritic complexity and excitability, ultimately culminating in depressive-like behaviors in adult mice.

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

Code

The paper links to its data, not to its authors' code: see the Data section.

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

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Data

Datasets cited

Data availability

The Single-cell RNA-seq and bulk RNA-seq that support the findings of this study are available at Gene Expression Omnibus under accession number GSE282783 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE282783). Proteome data are available at iPROX (PXD058068, https://www.iprox.cn//page/project.html?id=IPX0010286000). Human109 (fetal to adult) and mouse110,111 PFC Single-cell RNA-sequencing data (postnatal and adult) are from GEO datasets. No custom code was used. Source data are provided with Source Data file. All other data are available from the corresponding authors upon request. Source data are provided with this paper.

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 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 22 authors, 2 keywords, 16 MeSH terms, 1 funder, 110 references.

Cite

This paper

Jiang, X., Qi, Y., Yang, L., Yang, F., Guo, R., Li, L., Wang, K., Sun, L., Dai, D., Liu, H., Gao, Y., Sun, M., Song, X., Zhang, Z., Xu, Z., Luo, B., Xie, Y., Yang, Z., He, M., . . . Liu, G. (2026). Delayed astrocyte development impairs Sema6a-Plxna2/4-mediated astrocyte-neuron crosstalk and causes depressive-like behavior. Nature communications, 17(1), 8800. https://doi.org/10.1038/s41467-026-75697-z

BibTeX

@article{jiang2026delayed,
author = {Jiang, Xin and Qi, Yanqing and Yang, Lin and Yang, Feihong and Guo, Rongliang and Li, Liang and Wang, Kun and Sun, Lichen and Dai, Dan and Liu, Hanchen and Gao, Yanjing and Sun, Mengge and Song, Xiaolei and Zhang, Zhuangzhi and Xu, Zhejun and Luo, Bin and Xie, Yunli and Yang, Zhengang and He, Miao and Qi, Dashi and Zhang, Xiaodan and Liu, Guoping},
title = {{Delayed astrocyte development impairs Sema6a-Plxna2/4-mediated astrocyte-neuron crosstalk and causes depressive-like behavior}},
journal = {Nature communications},
year = {2026},
month = jul,
volume = {17},
number = {1},
pages = {8800},
publisher = {Nature Publishing Group},
issn = {2041-1723},
doi = {10.1038/s41467-026-75697-z},
url = {https://doi.org/10.1038/s41467-026-75697-z},
pmid = {42471335},
pmcid = {PMC13494039}
}

RIS

TY - JOUR
AU - Jiang, Xin
AU - Qi, Yanqing
AU - Yang, Lin
AU - Yang, Feihong
AU - Guo, Rongliang
AU - Li, Liang
AU - Wang, Kun
AU - Sun, Lichen
AU - Dai, Dan
AU - Liu, Hanchen
AU - Gao, Yanjing
AU - Sun, Mengge
AU - Song, Xiaolei
AU - Zhang, Zhuangzhi
AU - Xu, Zhejun
AU - Luo, Bin
AU - Xie, Yunli
AU - Yang, Zhengang
AU - He, Miao
AU - Qi, Dashi
AU - Zhang, Xiaodan
AU - Liu, Guoping
TI - Delayed astrocyte development impairs Sema6a-Plxna2/4-mediated astrocyte-neuron crosstalk and causes depressive-like behavior
T2 - Nature communications
J2 - Nat Commun
PY - 2026
DA - 2026/07/18
VL - 17
IS - 1
SP - 8800
SN - 2041-1723
PB - Nature Publishing Group
DO - 10.1038/s41467-026-75697-z
UR - https://doi.org/10.1038/s41467-026-75697-z
LA - en
ER -

CSL-JSON

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