Aberrant expression of genes necessary for neuronal development and Notch signaling in an epileptic mind bomb zebrafish.

Mutation within an ubiquitin E3 ligase gene can lead to a failure in Notch signaling, excessive neurons, and depletion of neural progenitor cells in mind bomb mutants. Using mib(hi904) zebrafish, we reported seizures and a down-regulation of γ-aminobutyric acid (GABA) signaling pathway genes. A transcriptome analysis also identified differential expression pattern of genes related to Notch signaling and neurodevelopment. Here, we selected nine of these genes (her4.2, hes5, bhlhb5, hoxa5a, hoxb5b, dmbx1a, dbx1a, nxph1, and plxnd1) and performed a more thorough analysis of expression using conventional polymerase chain reaction, real-time polymerase chain reaction and in situ hybridization. Transgenic reporter fish (Gfap:GFP and Dlx5a-6a:GFP) were used to assess early brain morphology in vivo. Down-regulation of many of these genes was prominent throughout key structures of the developing mib(hi904) zebrafish brain including, but not limited to, the pallium, ventral thalamus, and optic tectum. Brain expression of Dlx5a-6a and Gfap was also reduced. In conclusion, these expression studies indicate a general down-regulation of Notch signaling genes necessary for proper brain development and suggest that these mutant fish could provide valuable insights into neurological conditions, such as Angelman syndrome, associated with ubiquitin E3 ligase mutation.

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