Translational Control of Growth and Apoptosis in C. Elegans Development by Initiation Factor Isoforms

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New gene expression is required for cells to begin to grow and divide (proliferation) or to alter their fate (differentiation). The development of egg and sperm (gametes) likewise involves crucial periods of gene expression and differentiation. Early cells divide and then differentiate into either sperm or oocytes. Gene transcription is active early in gametogenesis, but becomes silenced as cells enter meiosis, and thus mRNAs that have been stored during the proliferative phase become the sole means to produce new proteins. Developmentally important mRNAs become translated into protein on ribosomes in the oocyte, spermatocyte or embryo, and the new proteins direct either continued differentiation or cell death (apoptosis). This research project is focused on proteins called eIF4 factors, which contact the mRNAs to be translated as the first step in recruiting them to the protein synthesis machinery. Specifically, the activities of eIF4 factors that lead to new protein synthesis in gametes and embryos will be investigated. Animal model systems such as the soil-dwelling nematode worm, Caenorhabditis elegans, are essential in this research because they are generally simpler than human embryos. The C. elegans embryo develops from a fertilized egg to an organized multi-cellular embryo in a manner very similar to that of higher animals. Fortunately these worms have a far simpler body plan made up of just a few muscles, neurons, digestive and reproductive organs. More importantly in the present context, the critical genes required are very similar in this simple model system. Because protein synthesis mechanisms are well conserved in animals, research findings using C. elegans will shed light on gene expression in vertebrate gametes and embryos, where such methods are not feasible or practical.Broader Impact and Educational Benefit: This project directly impacts the education of a minority and a female graduate student who are completing Ph.D. thesis research in Dr. Keiper's laboratory, as well as Masters and undergraduate students from ECU's Biology and Chemistry departments. As in the past granting period, the project also involves collaborators and students from other universities and high schools with an interest in molecular gene expression during development. The research capitalizes on the lab's experience in the biochemistry of mRNA translation and provides broad laboratory training in molecular techniques, genetics and transgenesis to young scientists. These students find the C. elegans system both tractable and significantly more accessible intellectually than mammalian systems. They receive the greatest educational benefit from first-hand involvement in new discoveries as well as opportunities to present their findings and publish their accomplishments in scientific journals. In recent years, several students who participated in this project have taken positions in the biotechnology industry or entered graduate research/medical professional academic programs.