Dyslexia is a neurodevelopmental disorder that affects between 5% and 12% of school-aged children. Individuals with dyslexia have difficulties in learning to read despite normal IQ levels and adequate socio-economical and educational opportunities. Dyslexia has a strong genetic component, but only a few candidate genes have been characterized to date. The KIAA0319 gene is a strong dyslexia candidate found to be associated with dyslexia in independent studies. The KIAA0319 genetic variants associated with dyslexia reside in a regulatory region. Studies in rat suggested that this gene is required for neuronal migration during early cortex formation. The KIAA0319-like (KIAA0319L) is a KIAA0319 homolog in structure and has recently been shown to play a role in dyslexia. I used zebrafish as a model organism both to study the effects of non-coding variants and to characterise kiaa0319 gene function. I used Gateway Tol2 technology to study the role of regulatory sequences. While these experiments led to inconclusive results, they highlighted some of the challenges but also the feasibility of using zebrafish as model organism to study genetic associations. In parallel, I studied the kiaa0319 function with knockout and knockdown experiments. Additionally, I conducted a detailed gene expression analysis with different in situ hybridisation protocols showing kiaa0319 ubiquitous expression in the whole embryo before 12 hours post fertilisation, with later specification to the eyes, brain, otic vesicle and notochord. Additionally, I have tested for the expression of kiaa0319l and showed similar expression pattern to the kiaa0319, but with significantly lower expression of kiaa0319l in zebrafish notochord. My data show, for the first time, that kiaa0319 has stage-specific expression in the brain and notochord during zebrafish early development, suggesting kiaa0319 specific role in the development of these structures. These results are in line with recent mouse studies. With this project I support the idea of kiaa0319 role being extended beyond the brain function and propose a role for kiaa03019 in the visual system and in the notochord.

No description available.

Development of the vertebrate central nervous system is a complex process that relies on the accurate spatiotemporal distribution of signaling centers during embryogenesis. These signals provide cells with positional information, which is integrated via transcription factors and gene regulatory elements to generate a specific downstream gene expression profile that confers specific cellular functions. It is of interest to determine how cells acquire their unique spatiotemporal gene expression patterns. The wide variety of expression profiles established along the dorsoventral axis of the neural tube provides a great system to address this question. Recent advances in zebrafish transgenic technology, along with the phenomenon of a fish-specific genome duplication event, have been exploited here to provide an efficient way of identifying and characterizing gene regulatory elements. An identified neuronal-specific enhancer near the ladybird locus has been incorporated into a transgenic zebrafish strain driving fluorescent reporter protein expression in a subset of dorsal interneurons / Molecular Biology and Genetics

No description available.