Graduate Thesis Or Dissertation
 

Vitamin E and the alpha-tocopherol transfer protein during zebrafish embryogenesis

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  • Vitamin E was first described in 1922 as an unknown factor required for impregnated rats to carry their offspring to term. In fact, when vitamin E was chemically characterized it was given the name "tocopherol" derived from the Greek: tokos = childbirth; phero = to bear; and –ol, indicating an alcohol. Vitamin E is linked to animal health and wellness, maternal fertility and a human neurodegenerative condition, ataxia with vitamin E deficiency However, embryonic vitamin E requirements during development remained unknown. We hypothesized that vitamin E is critical, not only for the mother, but specifically by the embryo for proper development. To separate the embryonic and maternal requirements, we employed an innovative model for the study of vitamin E: the zebrafish. We began by formulating and testing the first fully defined diet sufficient for zebrafish health. We then removed vitamin E from the formula to create our E deficient (E-) diet, which, when fed to adult zebrafish (for >3 months), resulted in E- adults that produced viable, E- gametes. Deficient embryos initially developed normally; however, by 48 hours post fertilization (hpf), E- embryos developed severe malformations leading to significant mortality. Thus, we demonstrated for the first time an embryonic vitamin E requirement. We provided further insight into the embryonic vitamin E requirement by analyzing the transcriptional changes occurring prior to the observed malformations. The transcriptome revealed a putative mechanism of action for vitamin E in development, in which vitamin E deficiency leads to the dysregulation of key metabolic co-activators. Finally, to understand the trafficking of vitamin E, we identified the zebrafish α-tocopherol transfer protein (TTP). We demonstrated that the zebrafish TTP is homologous to its human counterpart, and its expression is both spatially and temporally regulated during embryonic development. Knocking down the expression of TTP, using morpholinos injected at the one-cell stage, resulted in early and severe malformations in the developing head and tail. Consequently we revealed a definitive role for TTP during development. Taken together the work described here presents a new direction for future research into the role of vitamin E and TTP in post-implantation development.
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