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<p>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<sup>+</sup> regeneration, and is accompanied by lower mitochondrial abundance of the Complex I assembly factor ECSIT. Restoring mitochondrial NAD<sup>+</sup> regeneration with MTS-<i>Lb</i>NOX, 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<sup>+</sup> 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.</p>

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Ligand-independent EPHA2 signaling sustains neural progenitors via ECSIT and NAD+

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月10日

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  • Tran Diem Nghi,
  • Truong Thi My Nhung,
  • Seunghyun Kim,
  • Jonghyeok Yun,
  • Nguyen Tran Nam Tien,
  • Ara Lee,
  • Minkyo Jung,
  • Eun Jin Jang,
  • Bon Seong Goo,
  • Jin Yeong Yoo,
  • Sung Ryong Shin,
  • Ji Young Mun,
  • Kyeng Min Park,
  • Nguyen Phuoc Long,
  • Cana Park,
  • Sang Ki Park

摘要

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.