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However, the pathogenic mechanisms underlying TUBB5 mutations remain incompletely understood. We generated tubb5 knockout zebrafish using CRISPR\/Cas9 genome editing technology. Homozygous mutants were lethality within two weeks post-fertilization along with developmental delay, craniofacial malformations, uncoordinated movement and increased seizure susceptibility. tubb5 knockout larvae also showed reduced locomotor activity and impair photomotor responses. Furthermore, tubb5 knockout larvae exhibited significantly attenuated locomotor activity under alternating light\/dark conditions compared to wild-type controls. Pharmacological intervention with carbamazepine and sodium valproate ameliorated both locomotor dysfunction and PTZ-induced seizure susceptibility in mutant larvae. Transcriptome analysis revealed that tubb5 knockout larvae showed upregulated expression of notch1a and her5, which inhibit neural progenitor differentiation. Whole-mount in situ hybridization demonstrated decreased neurogenin1 and huc positive neurons, while sox2 positive neurons were increased in tubb5 mutants, indicating disrupted neural progenitor differentiation. DAPT treatment rescued both developmental and locomotor deficits tubb5 knockout zebrafish. This study demonstrates that tubb5 regulates neural progenitor differentiation via the Notch signaling pathway and identifies DAPT as a potential therapeutic agent for disorders associated with human TUBB5 mutations.<\/jats:p>","DOI":"10.1093\/hmg\/ddag041","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T11:32:35Z","timestamp":1778585555000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>tubb5<\/i>\n                    knockout in zebrafish causes neurodevelopmental defects via notch pathways"],"prefix":"10.1093","volume":"35","author":[{"given":"Huihui","family":"Liu","sequence":"first","affiliation":[{"name":"Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology , Wuhan, Hubei, 430074 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