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Ligand-independent EPHA2 signaling sustains neural progenitors via ECSIT and NAD<sup/>.

Overview

Authors: Tran Diem Nghi1, Truong Thi My Nhung1,2, Seunghyun Kim1, Jonghyeok Yun1, Nguyen Tran Nam Tien3, Ara Lee4, Minkyo Jung5, Eun Jin Jang1, Bon Seong Goo1,6, Jin Yeong Yoo1, Sung Ryong Shin1, Ji Young Mun5, Kyeng Min Park4, Nguyen Phuoc Long3,7,8, Cana Park2, Sang Ki Park1
ORCID iDs: Nguyen Tran Nam Tien, Bon Seong Goo, Jin Yeong Yoo, Nguyen Phuoc Long, Sang Ki Park
  1. Department of Life Sciences, Pohang University of Science and Technology,Pohang, Republic of Korea
  2. Department of Biology, University of Massachusetts Amherst,Amherst, MA USA
  3. Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine,Busan, Republic of Korea
  4. Department of Biochemistry, Daegu Catholic University School of Medicine,Daegu, Republic of Korea
  5. Neural Circuit Research Group, Korea Brain Research Institute,Daegu, Republic of Korea
  6. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine,Baltimore, MD USA
  7. Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University,Taoyuan, Taiwan
  8. Molecular Medicine Research Center, Chang Gung University,Taoyuan, Taiwan
Institutions: Pohang University of Science and Technology (South Korea); University of Massachusetts Amherst (United States); Inje University (South Korea); Daegu Catholic University (South Korea); Korea Brain Research Institute (South Korea); Johns Hopkins University (United States); Chang Gung University (Taiwan)
Journal: EMBO reports, volume 27, issue 16, pages 4782-4823
Dates: received 7 May 2026; accepted 23 June 2026; published online 10 July 2026; in print August 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s44319-026-00858-6 · PMID 42432363 · PMCID PMC13503776 · OpenAlex W7167889969
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: mouse (organism)
Methods: Statistics, Smoothing, state filtering, decompositions, Preprocessing, Evoked potentials, Machine learning, fMRI & imaging, Single-unit activity, calcium imaging
Keywords: Metabolism, Neuroscience
MeSH: NAD*, Neural Stem Cells*, Receptor, EphA2*, Signal Transduction*, Animals, Ligands, Mice, Mitochondria (* major topic)
Topic: Axon Guidance and Neuronal Signaling (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex
Funding: National Research Foundation of Korea (K-Brain Project (RS-2023-00265581), Innovation Research Center (RS-2023-00260454), Mid-career Researcher Program (RS-2024-00353657)); HKUST-POSTECH Joint Research Seed Grant Program and Global Knowledge Network Awards
Citations: not cited yet (Europe PMC); 43 references in the paper
Research resources: RRID:CVCL_9773, MATLAB R2022b RRID:SCR_001622, RRID:SCR_001905, GraphPad Prism RRID:SCR_002798, Imaris RRID:SCR_007370, Olympus cellSens software RRID:SCR_016238, Q-Exactive Plus Orbitrap RRID:SCR_020556, RRID:SCR_021365

Abstract

Embryonic neural stem and progenitor cells occupy a specialized niche along the lateral ventricles, where receptors on their apical membrane sense extracellular cues essential for preserving progenitor identity. How such surface signals are coupled to mitochondrial metabolism remains unclear. Here, we identify EPHA2 as a receptor enriched in cortical progenitors and show that disruption of its non-canonical, ligand-independent signaling compromises progenitor maintenance in vivo. EPHA2 perturbation reduces mitochondrial respiration, Complex I activity, and mitochondrial NAD+ regeneration, and is accompanied by lower mitochondrial abundance of the Complex I assembly factor ECSIT. Restoring mitochondrial NAD+ regeneration with MTS-LbNOX, or restoring mitochondrial ECSIT with ECSIT WT—but not a mitochondrial targeting-deficient mutant—attenuates the progenitor defects caused by EPHA2 perturbation. Maternal supplementation with NAD+ or its precursor NMN similarly mitigates these developmental defects. We further identify a PP2A-sensitive ECSIT phospho-state, including T179, that is consistent with regulated mitochondrial ECSIT accumulation downstream of EPHA2. Together, these findings support a model in which EPHA2 helps maintain embryonic cortical progenitors by sustaining ECSIT-dependent Complex I-linked mitochondrial redox homeostasis.

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

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Data availability

The mass spectrometry proteomics data reported in this study have been deposited in the ProteomeXchange Consortium via the jPOST partner repository under accession code “PXD079834 (http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD079834)” for ProteomeXchange and “JPST004710” for jPOST. Other data are available from the corresponding author on request.

The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44319-026-00858-6 (https://www.ebi.ac.uk/biostudies/sourcedata/studies/S-SCDT-10_1038-S44319-026-00858-6).

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, 16 authors, 2 keywords, 8 MeSH terms, 2 funders, 43 references, 8 RRIDs.

Cite

This paper

Diem Nghi, T., My Nhung, T. T., Kim, S., Yun, J., Tien, N. T. N., Lee, A., Jung, M., Jang, E. J., Goo, B. S., Yoo, J. Y., Shin, S. R., Mun, J. Y., Park, K. M., Phuoc Long, N., Park, C., & Park, S. K. (2026). Ligand-independent EPHA2 signaling sustains neural progenitors via ECSIT and NAD<sup/>. EMBO reports, 27(16), 4782-4823. https://doi.org/10.1038/s44319-026-00858-6

BibTeX

@article{diemnghi2026ligand,
author = {Diem Nghi, Tran and My Nhung, Truong Thi and Kim, Seunghyun and Yun, Jonghyeok and Tien, Nguyen Tran Nam and Lee, Ara and Jung, Minkyo and Jang, Eun Jin and Goo, Bon Seong and Yoo, Jin Yeong and Shin, Sung Ryong and Mun, Ji Young and Park, Kyeng Min and Phuoc Long, Nguyen and Park, Cana and Park, Sang Ki},
title = {{Ligand-independent EPHA2 signaling sustains neural progenitors via ECSIT and NAD<sup/>}},
journal = {EMBO reports},
year = {2026},
month = jul,
volume = {27},
number = {16},
pages = {4782--4823},
publisher = {Nature Publishing Group},
issn = {1469-221X},
doi = {10.1038/s44319-026-00858-6},
url = {https://doi.org/10.1038/s44319-026-00858-6},
pmid = {42432363},
pmcid = {PMC13503776}
}

RIS

TY - JOUR
AU - Diem Nghi, Tran
AU - My Nhung, Truong Thi
AU - Kim, Seunghyun
AU - Yun, Jonghyeok
AU - Tien, Nguyen Tran Nam
AU - Lee, Ara
AU - Jung, Minkyo
AU - Jang, Eun Jin
AU - Goo, Bon Seong
AU - Yoo, Jin Yeong
AU - Shin, Sung Ryong
AU - Mun, Ji Young
AU - Park, Kyeng Min
AU - Phuoc Long, Nguyen
AU - Park, Cana
AU - Park, Sang Ki
TI - Ligand-independent EPHA2 signaling sustains neural progenitors via ECSIT and NAD<sup/>
T2 - EMBO reports
J2 - EMBO Rep
PY - 2026
DA - 2026/07/10
VL - 27
IS - 16
SP - 4782
EP - 4823
SN - 1469-221X
PB - Nature Publishing Group
DO - 10.1038/s44319-026-00858-6
UR - https://doi.org/10.1038/s44319-026-00858-6
LA - en
ER -

CSL-JSON

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