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<p>Neuronal maturation involves a tightly regulated cessation of growth and acquisition of polarity, ultimately leading to synapse formation. While essential for circuit stability, maturation marks the loss of regenerative capacity after central nervous system (CNS) injury. The molecular programs coupling maturation to regenerative decline remain incompletely understood. Here, we show that the transcriptional and epigenetic signatures enabling axon growth in dorsal root ganglion (DRG) neurons are lost as they transition from immature, non-polarized cells to mature, pseudo-unipolar neurons. We identify the transcriptional co-regulator CITED2 as a key epigenetic switch, active in immature and regenerating DRG neurons but silent after non-regenerative spinal cord injury (SCI). Cited2 overexpression reactivates growth programs, enhancing regeneration in vivo after SCI. Mechanistically, CITED2 reinstates developmental epigenetic and transcriptional profiles, decoupling maturation from regenerative failure. Pharmacogenomic screening identified CITED2 as a target of the clinically approved HDAC inhibitor Panobinostat, which promoted axonal growth, sprouting, and functional recovery post-injury. These findings position CITED2 as a key regulator of sensory neuron plasticity and a novel therapeutic target for CNS repair.</p>

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CITED2 is a druggable epigenetic switch coupling neuronal maturation to regenerative decline

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月23日

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  • Franziska Müller,
  • Eilidh McLachlan,
  • Ana Catarina Costa,
  • Jia Qu,
  • Bishal Shrestha,
  • Zheng Wang,
  • Francesco De Virgiliis,
  • Thomas Haynes Hutson,
  • Luming Zhou,
  • Guiping Kong,
  • Jessica S Chadwick,
  • Paolo La Montanara,
  • Zhulin Yuan,
  • Nejc Haberman,
  • Monica M Sousa,
  • Ilaria Palmisano,
  • Simone Di Giovanni

摘要

Neuronal maturation involves a tightly regulated cessation of growth and acquisition of polarity, ultimately leading to synapse formation. While essential for circuit stability, maturation marks the loss of regenerative capacity after central nervous system (CNS) injury. The molecular programs coupling maturation to regenerative decline remain incompletely understood. Here, we show that the transcriptional and epigenetic signatures enabling axon growth in dorsal root ganglion (DRG) neurons are lost as they transition from immature, non-polarized cells to mature, pseudo-unipolar neurons. We identify the transcriptional co-regulator CITED2 as a key epigenetic switch, active in immature and regenerating DRG neurons but silent after non-regenerative spinal cord injury (SCI). Cited2 overexpression reactivates growth programs, enhancing regeneration in vivo after SCI. Mechanistically, CITED2 reinstates developmental epigenetic and transcriptional profiles, decoupling maturation from regenerative failure. Pharmacogenomic screening identified CITED2 as a target of the clinically approved HDAC inhibitor Panobinostat, which promoted axonal growth, sprouting, and functional recovery post-injury. These findings position CITED2 as a key regulator of sensory neuron plasticity and a novel therapeutic target for CNS repair.