Cytokinesis and RNA Segregation in Zebrafish Development

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DESCRIPTION (provided by applicant): Cytokinesis, the physical process that divides daughter cells, is of critical importance to development and growth regulation. In many instances, cytokinesis is coupled with the asymmetric segregation of cellular determinants, which in turn results in the functional diversification of cell types. A basic question in biology is to understand the molecular mechanisms underlying the segregation of cell fate determinants, in particular the germ plasm, a specialized cytoplasm that confers the germ cell fate. Systematic screens for maternal-effect mutations in the zebrafish, Danio rerio, have identified genes that affect the processes of cytokinesis and germ plasm segregation, which in this organism are intimately linked. To our knowledge, these are the first identified mutations in vertebrate genes required for cytokinesis. This proposal focuses on the analysis of the function of one of these genes, Cellular Island, which we show codes for Aurora B kinase, a chromosomal passenger protein involved in furrow initiation. Functional analysis of this gene suggests that it has an essential role in furrow formation in lateral, but not medial, regions of the embryonic blastodisc. We will test the hypothesis that furrow-inducing signals from different microtubule-based structures, possibly through the action of distinct downstream mediators such as Aurora B kinase, are required for cytokinesis in separate regions of the blastodisc. The proposed research will also determine the precise roles of these signals in the process of germ plasm recruitment to the forming furrow. The understanding of these mechanisms will provide insights on both a fundamental cellular process (cytokinesis) and a fundamental developmental process (germ plasm segregation), and the functional relationship between them in the early vertebrate embryo. The proposed research addresses fundamental mechanisms of cell division and the determination of cell fate, in particular, the specification of the germ cells. Knowledge acquired through these studies will lead to progress in therapies that alleviate health problems related to reproductive biology, cancer, and stem cell and tissue development.