The Role of Autism Susceptibility Gene Topoisomerase 3B (top3b) in Zebrafish Neural Development

Autism Spectrum Disorder (ASD) is known to cause varied behavioral defects in affected individuals. Biological causes underlying these defects are poorly understood. Investigations have shown ASD as a result of abnormal brain development, in regards to genetic alterations during crucial developmental stages. Genetic mutations in genes such as neurotrophins and neurobeachins have been found to correlate with ASD behaviors. A more recent study has identified that mutations in topoisomerase3b (top3b) induce certain neurodevelopmental disorder characteristics. Phenotypic defects demonstrating neurodevelopmental deficiencies in top3b mutants have been observed in fruit flies and mouse neuronal cell cultures and lean towards a role in synapse formations. However, the in vivo roles of top3b in vertebrate neural development have not been clearly understood. Therefore, our current research focuses on an in vivo study using zebrafish embryos as a vertebrate model system to identify top3b roles in early neurological development. RNA in situ hybridization has identified top3b expression in the forebrain, notochord, and retinotectal pathways. Anti-sense morpholino-based knockdowns reveal defasciculation of spinal motor axons, expanded notochord, and failure of retinal lamination and retino-tectal pathway. Location of top3b expression and defects seen in morpholino knockdowns almost directly correlate, further implicating strong roles for top3b activity in olfactory neuron/axon development, neuromuscular synapse formation, and retinal layer formation. Knowing these roles in neural development will further aid in understanding a potential source of the spectrum of developmental disabilities that are displayed