CYTODEV · Functions of the midbody ring in embryogenesis and tumorigenesis

There is ample evidence for important roles of cytokinesis in animal development besides ensuring faithful division of daughter cells. However, these additional functions and their mechanistic basis are not well understood. With the work proposed here we will elucidate roles of cytokinesis in differentiation and tumorigenesis. We will focus on the function of the midbody ring (MR), a protein-dense organelle that forms at the site of abscission during cytokinesis. This organelle forms only once during cell division and thus can only be inherited by one of the two daughter cells, creating an inherent asymmetry to cytokinesis. MRs have been implicated in sequestering stem-cell markers and as mediators of differentiation and pluripotency in vitro, the underlying molecular mechanisms and in vivo functions are not clear.We propose a multidisciplinary approach that combines microscopy, computational image analysis, and developmental genetics to analyze how asymmetric MR inheritance affects differentiation and tumorigenesis. We will transfer image analysis technology to the host institution that allows us to use Caenorhabditis elegans as a developmental model for automated cell tracking and fate mapping, to quantitatively analyze the function of MRs in development: We will investigate how asymmetric MR inheritance is regulated during C. elegans embryogenesis and tumor formation and how asymmetric MR distribution affects major differentiation decisions. C. elegans is ideally suited for these experiments since we know the entire embryonic cell lineage, all major differentiation decisions, can induce well-defined tumors, and have powerful genetic tools to manipulate development.We expect that the main results of our work will be of great general interest since they will for the first time address the role of MRs in vivo based on a quantitative approach, thus improving our understanding how asymmetries in cytokinesis can affect normal development and cancer