Disrupting fzd9b in Zebrafish Recapitulates Stress- and Anxiety-Like Behaviours Relevant to Williams Syndrome.

Overview

1. Departament de Biologia Cel·lular, Biologia Funcional i Antropologia Física, Universitat de València,46100 Burjassot, València Spain
2. School of Biological and Behavioural Sciences, Queen Mary University of London,London, E1 4NS UK
3. Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London,London, UK

Abstract

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 caused by a hemizygous microdeletion on chromosome 7q11.23. Among the affected genes, FZD9 is implicated in neural development and synaptic function. Thus, we postulated that disruption of FZD9 might contribute to the behavioural features of WS, and that pharmacological modulation of Wnt signalling, particularly the canonical β-catenin pathway, could offer therapeutic potential. We generated two zebrafish lines carrying predicted loss-of-function alleles of fzd9b, a zebrafish orthologue of FZD9. Our results demonstrated that mutant fish exhibited altered expression of hypothalamic–pituitary–interrenal axis-related genes, increased neuronal branching, impaired habituation to acoustic startle, and increased anxiety-like behaviour in adulthood. Canonical Wnt/β-catenin pathway gene expression was also altered, together with the expression of other frizzled receptors; however, acute GSK-3 inhibition failed to rescue behavioural phenotypes under the conditions tested. These findings indicate that the selected acute treatment paradigm was insufficient to reverse the phenotype but do not exclude a contribution of canonical Wnt signalling. Expression of fzd9b, wnt5b, and tafa5l was upregulated, further supporting transcriptional dysregulation. Together, our results highlight a conserved role for Fzd9b in modulating stress reactivity and anxiety-like behaviour in zebrafish and support FZD9 as a contributor to WS-associated neurobehavioural alterations.

Supplementary Information: The online version contains supplementary material available at 10.1007/s12035-026-06127-w.

Reproduced under the paper's license (CC BY), from the paper cited above.

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• zenodo:10548489, at Zenodo; found in “Data Availability”

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Generated data can be found at https://zenodo.org/ (10.5281/zenodo.10548489).

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 2, 28 September 2026

• Publisher: n/a → Springer Science+Business Media

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 4 keywords, 10 MeSH terms, 5 funders, 70 references.

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This paper

Torres-Perez, J. V., Leggieri, A., Wang, X., Kehoe, A., Van Schalkwyk, L., Mech, A. M., Anagianni, S., Havelange, W., & Brennan, C. H. (2026). Disrupting fzd9b in Zebrafish Recapitulates Stress- and Anxiety-Like Behaviours Relevant to Williams Syndrome. Molecular neurobiology, 63(1), 853. https://doi.org/10.1007/s12035-026-06127-w

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