Genetic Control of Tubulin Function in Development

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DESCRIPTION:A fundamental question in biology is how functional three-dimensional cell structure is formed. The proposed research addresses this question by genetic and molecular studies of microtubule function in Drosophila melanogaster. Microtubules are ubiquitous eukaryotic organelles required for many cellular processes, including cell shape, cell division, and the motility of cilia and flagella. The basic subunit of microtubules is the alpha, Beta-tubulin heterodimer. Multicellular eukaryotes express multiple tubulin isoforms encoded in multi-gene families; additional tubulin diversity is generated by post-translational modifications. Each microtubule structure is unique in supramolecular architecture, mode of function, and total spectrum of constituent proteins. Assembly of different microtubule-based structures thus depends on interactions between tubulin heterodimers, and between tubulins and other proteins. The proposed research focuses on the role of tubulin diversity in determining the specificity of microtubule assembly and function. Because microtubule arrays are similar in all organisms, the results obtained in Drosophila are directly relevant to understanding microtubule function in other species, including vertebrates. The first goal of the proposed research is to determine the role of tubulin primary structure in specifying the architecture of different classes of microtubules. These studies use as a model system analysis of the multiple microtubule processes in spermatogenesis mediated by the testis-specific beta2-tubulin isoform. The primary focus is assembly of the motile axoneme, a deeply conserved organelle present in animals, plants, and protists. A major objective is to determine the molecular mechanisms by which distinct tubulin-associated components of the sperm flagella axoneme are specified. The second goal of the proposed work is to determine the role of differential expression of different tubulin isoforms in development and cell differentiation. These studies focus on analysis of the function of the essential, structurally divergent beta3-tubulin isoform in neuronal patterning in the developing adult visual system and in the larval mechanosensory organs. Transient beta3 expression during differentiation has permanent consequences for cell function, even when beta3 is no longer present. The primary aim is to determine how transient expression of beta3-tubulin during development modulates the microtubule cytoskeleton in the differentiated cell.