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866859.pdf (2.3 MB)

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2025-11-19

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cc-by-nc-nd (c) Leggieri, A. et al., 2025
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/224831

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

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https://doi.org/10.1038/s41398-025-03703-x

Resum

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.

Matèries

Mutagènesi, Hidrocortisona

Matèries (anglès)

Mutagenesis, Hydrocortisone

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Articles publicats en revistes (Genètica, Microbiologia i Estadística)
Articles publicats en revistes (Institut de Biomedicina (IBUB))

Citació

LEGGIERI, Adele, GARCÍA-GONZÁLEZ, Judit, HOSSEINIAN, Saeedeh, ASHDOWN, Peter, ANAGIANNI, Sofia, WANG, Xian, HAVELANGE, William, FERNÀNDEZ CASTILLO, Noèlia, CORMAND RIFÀ, Bru, BRENNAN, Caroline h.. 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. _Translational Psychiatry_. 2025. Vol. 15, núm. 1-15. [consulta: 3 de gener de 2026]. ISSN: 2158-3188. [Disponible a: https://hdl.handle.net/2445/224831]

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