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. 2025 Mar;62(3):3024-3039.
doi: 10.1007/s12035-024-04448-2. Epub 2024 Aug 31.

tubg1 Somatic Mutants Show Tubulinopathy-Associated Neurodevelopmental Phenotypes in a Zebrafish Model

Ozge Cark #  1   2   3 , Esra Katkat #  1   2 , Ipek Aydogdu  1   4 , Evin Iscan  1   2 , Yavuz Oktay  1   2   5 , Gunes Ozhan  6   7
Affiliations

tubg1 Somatic Mutants Show Tubulinopathy-Associated Neurodevelopmental Phenotypes in a Zebrafish Model

Ozge Cark et al. Mol Neurobiol. 2025 Mar.

Abstract

Development of the multilayered cerebral cortex relies on precise orchestration of neurogenesis, neuronal migration, and differentiation, processes tightly regulated by microtubule dynamics. Mutations in tubulin superfamily genes have been associated with tubulinopathies, encompassing a spectrum of cortical malformations including microcephaly and lissencephaly. Here, we focus on γ-tubulin, a pivotal regulator of microtubule nucleation encoded by TUBG1. We investigate its role in brain development using a zebrafish model with somatic tubg1 mutation, recapitulating features of TUBG1-associated tubulinopathies in patients and mouse disease models. We demonstrate that γ-tubulin deficiency disrupts neurogenesis and brain development, mirroring microcephaly phenotypes. Furthermore, we uncover a novel potential regulatory link between γ-tubulin and canonical Wnt/β-catenin signaling, with γ-tubulin deficiency impairing Wnt activity. Our findings provide insights into the pathogenesis of cortical defects and suggest that γ-tubulin could be a potential target for further research in neurodevelopmental disorders, although challenges such as mode of action, specificity, and potential side effects must be addressed.

Keywords: Neurodevelopmental disorder; Tubulin gamma 1; Tubulinopathies; Wnt/β-catenin signaling; Zebrafish.

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Conflict of interest statement

Declarations. Ethics Approval: Zebrafish larvae up to 5 dpf were used in this study, which was reviewed and approved by IBG-AELEC. According to the European Commission Directive 2010/63/EU, experimentation on fish embryos at their earliest life stages is not regulated as animal experiments ( https://eur-lex.europa.eu/eli/dir/2010/63/2019-06-26 ). This includes zebrafish embryos and early larval stages until they are free-swimming and independently feeding, corresponding to 5 dpf (days post-fertilization) when raised at 28.5 °C. Consent to Participate and Consent for Publication: This study did not involve human subjects. Competing Interests: The authors declare no competing interests.

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