Biology subjects

Leggieri, A.

Publications and source records attributed to Leggieri, A..

3 recordsLinked to original sources

bioRxiv2024

rbfox1 loss of function in zebrafish leads to dysregulation in bdnf/trkb2 and pac1a expression resulting in HPI axis hyperactivation, altered stress response and allostatic overload

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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/616976v5_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@17e3bbcorg.highwire.dtl.DTLVardef@83f0eeorg.highwire.dtl.DTLVardef@3e9985org.highwire.dtl.DTLVardef@1d116ff_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2024

Disrupting fzd9b in zebrafish recapitulates stress- and anxiety-like behaviours associated with Williams syndrome

Williams syndrome (WS) is a multifaceted developmental disorder characterized by a spectrum of physical and intellectual traits. Individuals with WS exhibit friendly, impulsive, and hyper-social behaviours, often coupled with anxiety. WS is attributed to a microdeletion on chromosome 7q11.23, affecting several genes, including FZD9, which plays an important role in neurodevelopment. Thus, we postulated that disruptions in FZD9 might contribute to the behavioural features of WS including anxiety, and that pharmacological interventions targeting Wnt signalling, particularly the canonical pathway, might hold therapeutic potential for WS and related conditions. To test our hypothesis, we generated two mutant zebrafish lines with fzd9b disruptions. Our behavioural analysis revealed significant differences in stress- and anxiety-related responses at both larval and adult stages. Our attempt to restore stress reactivity by manipulating the Wnt/{beta}-catenin pathway using a GSK-3 inhibitor was unsuccessful. Our qPCR data indicated a compensatory mechanism involving the upregulation of fzd9b, wnt5b, and tafa5l genes, potentially contributing to the observed phenotypes. These findings highlight the role of Fzd9b in modulating anxiety responses in zebrafish, offering potential avenues for novel therapeutics to address the neurological features of WS and related disorders. Summary statementsO_LIWe created mutant zebrafish lines to study stress reactivity and social behaviour, mirroring features found in Williams Syndrome (WS). C_LIO_LIConfirmation of fzd9b disruption revealed altered anxiety responses in larval and adult zebrafish. C_LIO_LIMarginal sociability increase was observed in the heterozygous fish for one of the two lines generated. C_LIO_LIAttempts to restore stress reactivity via the Wnt/{beta}-catenin pathway manipulation were unsuccessful. C_LIO_LIWe have identified compensation mechanisms involving upregulation of wnt5b and tafa5l genes. C_LI

neuroscience↗

bioRxiv2023

Pleiotropic contribution of rbfox1 to psychiatric and neurodevelopmental phenotypes in a zebrafish model

RBFOX1 is a highly pleiotropic gene that contributes to several psychiatric and neurodevelopmental disorders. Both rare and common variants in RBFOX1 have been associated with several psychiatric conditions, but the mechanisms underlying the pleiotropic effects of RBFOX1 are not yet understood. Here we found that, in zebrafish, rbfox1 is expressed in spinal cord, mid- and hindbrain during developmental stages. In adults, expression is restricted to specific areas of the brain, including telencephalic and diencephalic regions with an important role in receiving and processing sensory information and in directing behaviour. To investigate the effect of rbfox1 deficiency on behaviour, we used rbfox1sa15940, a rbfox1 loss-of-function line. We found that rbfox1sa15940 mutants present hyperactivity, thigmotaxis, decreased freezing behaviour and altered social behaviour. We repeated these behavioural tests in a second rbfox1 loss-of-function line with a different genetic background, rbfox1del19, and found that rbfox1 deficiency affects behaviour similarly in this line, although there were some differences. rbfox1del19 mutants present similar thigmotaxis, but stronger alterations in social behaviour and lower levels of hyperactivity than rbfox1sa15940 fish. Taken together, these results suggest that rbfox1 deficiency leads to multiple behavioural changes in zebrafish that might be modulated by environmental, epigenetic and genetic background effects, and that resemble phenotypic alterations present in Rbfox1-deficient mice and in patients with different psychiatric conditions. Our study thus highlights the evolutionary conservation of rbfox1 function in behaviour and paves the way to further investigate the mechanisms underlying rbfox1 pleiotropy on the onset of neurodevelopmental and psychiatric disorders.

genetics↗