Scholarlink

<p>Mutations in the <i>RBFOX1</i> gene are associated with psychiatric disorders but how RBFOX1 influences psychiatric disorder vulnerability remains unclear. Recent studies showed that RBFOX proteins mediate the alternative splicing of PAC1, a critical HPA axis activator. Further, RBFOX1 dysfunction is linked to dysregulation of BDNF/TRKB, a pathway promoting neuroplasticity, neuronal survival and stress resilience. Hence, RBFOX1 dysfunction may increase psychiatric disorder vulnerability via HPA axis dysregulation, leading to disrupted development and allostatic overload. To test this hypothesis, we generated a zebrafish <i>rbfox1</i> loss of function (LoF) line and examined behavioural and molecular effects during development. We found that <i>rbfox1</i> LoF mutants exhibited hyperactivity, impulsivity and heightened arousal, alongside alterations in proliferation – traits associated with neurodevelopmental and stress-related disorders. In adults, loss of <i>rbfox1</i> function led to decreased fertility and survival, consistent with allostatic overload. At the molecular level, at larval stages <i>rbfox1</i> mutants showed increased cortisol levels and disrupted expression of key stress-related genes (<i>bdnf</i>, <i>trkb2, pac1a-hop</i>, <i>crhb, nr3c2</i>). Pharmacological intervention targeting TRKB restored <i>crhb</i> and <i>nr3c2</i> gene expression and hyperactive and hyperarousal behaviours. In adults, dysregulation of <i>crhb</i>, <i>nr3c2</i> and <i>bdnf</i>/<i>trkb2</i> genes was only seen following acute stress exposure. Our findings reveal a fundamental role for RBFOX1 in integrating stress responses through its regulation of BDNF/TRKB and neuroendocrine signalling.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

rbfox1 LoF mutants show disrupted bdnf/trkb2 and crhb/nr3c2 expression and increased cortisol levels during development coupled with signs of allostatic overload in adulthood

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月19日

查看全文
  • Adele Leggieri,
  • Judit García-González,
  • Saeedeh Hosseinian,
  • Peter Ashdown,
  • Sofia Anagianni,
  • Xian Wang,
  • William Havelange,
  • Noèlia Fernàndez-Castillo,
  • Bru Cormand,
  • Caroline H. Brennan

摘要

Mutations in the RBFOX1 gene are associated with psychiatric disorders but how RBFOX1 influences psychiatric disorder vulnerability remains unclear. Recent studies showed that RBFOX proteins mediate the alternative splicing of PAC1, a critical HPA axis activator. Further, RBFOX1 dysfunction is linked to dysregulation of BDNF/TRKB, a pathway promoting neuroplasticity, neuronal survival and stress resilience. Hence, RBFOX1 dysfunction may increase psychiatric disorder vulnerability via HPA axis dysregulation, leading to disrupted development and allostatic overload. To test this hypothesis, we generated a zebrafish rbfox1 loss of function (LoF) line and examined behavioural and molecular effects during development. We found that rbfox1 LoF mutants exhibited hyperactivity, impulsivity and heightened arousal, alongside alterations in proliferation – traits associated with neurodevelopmental and stress-related disorders. In adults, loss of rbfox1 function led to decreased fertility and survival, consistent with allostatic overload. At the molecular level, at larval stages rbfox1 mutants showed increased cortisol levels and disrupted expression of key stress-related genes (bdnf, trkb2, pac1a-hop, crhb, nr3c2). Pharmacological intervention targeting TRKB restored crhb and nr3c2 gene expression and hyperactive and hyperarousal behaviours. In adults, dysregulation of crhb, nr3c2 and bdnf/trkb2 genes was only seen following acute stress exposure. Our findings reveal a fundamental role for RBFOX1 in integrating stress responses through its regulation of BDNF/TRKB and neuroendocrine signalling.