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<p>The pituitary intermediate lobe (IL) is a surprisingly understudied pituitary region. Here, we find that chromatin-binding protein PHF6 is enriched in the pituitary IL and plays a crucial role in regulating stress susceptibility in mice. Conditional knockout of <i>Phf6</i> in PHF6-positive IL cells (<sup>IL</sup>PHF6 cells) significantly reduces acute stress-induced anxiety-like behaviors and chronic stress-induced depression-like behaviors by impairing cellular activation and the release of stress-related hormones. Mechanistically, conditional knockout of <i>Phf6</i> in the pituitary IL cells downregulates the calcium channel β3 subunit and suppresses transcription of stress-responsive genes. Chemogenetic inhibition of <sup>IL</sup>PHF6 cells reduces stress susceptibility, whereas activation of these cells increases anxiety-like behaviors. Circuit tracing demonstrates that <sup>IL</sup>PHF6 cells receive direct synaptic inputs from CRH-expressing neurons in the hypothalamus paraventricular nucleus (PVN), positioning <sup>IL</sup>PHF6 cells as a crucial interface between neural stress signals and endocrine output. These findings reveal a previously unknown mechanism in the regulation of stress susceptibility that operates through anxiogenic <sup>IL</sup>PHF6 cells, providing a perspective for understanding how stress susceptibility is molecularly tuned.</p>

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Regulation of stress susceptibility by chromatin-binding protein PHF6 in the pituitary intermediate lobe

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月6日

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  • Bing Liu,
  • Jingjie Wang,
  • Xiaohua Wu,
  • Linhua Gan,
  • Jingjing Sun,
  • Guangzhong Wang,
  • Qian Li,
  • Ju Huang

摘要

The pituitary intermediate lobe (IL) is a surprisingly understudied pituitary region. Here, we find that chromatin-binding protein PHF6 is enriched in the pituitary IL and plays a crucial role in regulating stress susceptibility in mice. Conditional knockout of Phf6 in PHF6-positive IL cells (ILPHF6 cells) significantly reduces acute stress-induced anxiety-like behaviors and chronic stress-induced depression-like behaviors by impairing cellular activation and the release of stress-related hormones. Mechanistically, conditional knockout of Phf6 in the pituitary IL cells downregulates the calcium channel β3 subunit and suppresses transcription of stress-responsive genes. Chemogenetic inhibition of ILPHF6 cells reduces stress susceptibility, whereas activation of these cells increases anxiety-like behaviors. Circuit tracing demonstrates that ILPHF6 cells receive direct synaptic inputs from CRH-expressing neurons in the hypothalamus paraventricular nucleus (PVN), positioning ILPHF6 cells as a crucial interface between neural stress signals and endocrine output. These findings reveal a previously unknown mechanism in the regulation of stress susceptibility that operates through anxiogenic ILPHF6 cells, providing a perspective for understanding how stress susceptibility is molecularly tuned.