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.
Por:
Leggieri A, García-González J, Hosseinian S, Ashdown P, Anagianni S, Wang X, Havelange W, Fernandez-Castillo N, Cormand B and Brennan CH
Publicada:
19 nov 2025
Ahead of Print:
19 nov 2025
Resumen:
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.
Filiaciones:
Leggieri A:
Centre for Brain and Behaviour, School of Biological and Behavioural Sciences, Queen Mary University of London, Mile End Rd, London, E1 4NS, UK
García-González J:
Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, New York City, NY, 10029, USA
Hosseinian S:
Centre for Brain and Behaviour, School of Biological and Behavioural Sciences, Queen Mary University of London, Mile End Rd, London, E1 4NS, UK
Ashdown P:
Centre for Brain and Behaviour, School of Biological and Behavioural Sciences, Queen Mary University of London, Mile End Rd, London, E1 4NS, UK
Anagianni S:
Centre for Brain and Behaviour, School of Biological and Behavioural Sciences, Queen Mary University of London, Mile End Rd, London, E1 4NS, UK
Wang X:
Centre for Brain and Behaviour, School of Biological and Behavioural Sciences, Queen Mary University of London, Mile End Rd, London, E1 4NS, UK
Havelange W:
Centre for Brain and Behaviour, School of Biological and Behavioural Sciences, Queen Mary University of London, Mile End Rd, London, E1 4NS, UK
Fernandez-Castillo N:
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalunya, 08028, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Catalunya, 08028, Spain
Institut de recerca Sant Joan de Déu, Espluges de Llobregat, Catalunya, 08950, Spain
Cormand B:
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalunya, 08028, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Catalunya, 08028, Spain
Institut de recerca Sant Joan de Déu, Espluges de Llobregat, Catalunya, 08950, Spain
Brennan CH:
Centre for Brain and Behaviour, School of Biological and Behavioural Sciences, Queen Mary University of London, Mile End Rd, London, E1 4NS, UK
Green Submitted, gold
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