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<p>Pathogenic variants in human <i>KCTD3</i> are associated with severe neurodevelopmental disorders characterized by early-onset seizures, developmental delay, hypotonia, and cerebellar hypoplasia, but the underlying mechanisms remain unclear. Here we show that KCTD3 regulates neuronal structural organization through DAAM1, a protein involved in actin cytoskeleton assembly. In <i>Kctd3</i>-deficient neurons, DAAM1 protein levels are reduced, the axon initial segment is abnormally organized, and neurite growth and growth cone morphology are impaired. These defects are rescued by DAAM1 overexpression. Systemic <i>Kctd3</i> depletion also disrupts axon initial segment organization and motor axon innervation at neuromuscular junctions, leading to motor dysfunction and growth impairment in mice. These findings identify a KCTD3-DAAM1 pathway required for neuronal structural development and provide a framework for understanding how <i>KCTD3</i> deficiency contributes to neurodevelopmental disorders.</p>

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KCTD3 deficiency disrupts axon initial segment organization and neurite outgrowth in a neurodevelopmental disorder mouse model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月7日

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  • Yeonsoo Oh,
  • Youngha Lee,
  • Hoyong Jin,
  • Marcello Scala,
  • Valeria Capra,
  • Annalaura Torella,
  • Vincenzo Nigro,
  • Bertrand Isidor,
  • Frédéric Tran Mau-Them,
  • René G. Feichtinger,
  • Johannes A. Mayr,
  • Saskia B. Wortmann,
  • Hyeyoon Kim,
  • Dohyun Han,
  • Jin Sook Lee,
  • Jong-Hee Chae,
  • Murim Choi,
  • Yongcheol Cho

摘要

Pathogenic variants in human KCTD3 are associated with severe neurodevelopmental disorders characterized by early-onset seizures, developmental delay, hypotonia, and cerebellar hypoplasia, but the underlying mechanisms remain unclear. Here we show that KCTD3 regulates neuronal structural organization through DAAM1, a protein involved in actin cytoskeleton assembly. In Kctd3-deficient neurons, DAAM1 protein levels are reduced, the axon initial segment is abnormally organized, and neurite growth and growth cone morphology are impaired. These defects are rescued by DAAM1 overexpression. Systemic Kctd3 depletion also disrupts axon initial segment organization and motor axon innervation at neuromuscular junctions, leading to motor dysfunction and growth impairment in mice. These findings identify a KCTD3-DAAM1 pathway required for neuronal structural development and provide a framework for understanding how KCTD3 deficiency contributes to neurodevelopmental disorders.