MitoScaling · Mitotic scaling to cell size diversity during vertebrate embryonic development

Mitotic scaling to cell size diversity during vertebrate embryonic development

Multicellular eukaryotes reproduce through the combination of a male and a female gamete, that once combined generate a one cell entity called the zygote. From this stage onwards, the zygote goes through multiple rounds of mitotic divisions to increase cell number that later will differentiate in different tissues and organs that will constitute the adult organism. Several studies have shown that human and mice early embryonic divisions are highly error prone and this could be associated with embryo malformation and potential miscarriage. Therefore, the first rounds of division of an embryo are decisive to insure its viability and it is of great interest to understand how they are regulated. Early embryonic development is still a mysterious process, mainly because of the difficulty (technical and ethical) in obtaining early embryos from mammalian organisms, such as mice or humans. In this project we use zebrafish embryos as a eukaryotic model system that develops outside the mother and can be easily observed under the microscope. These have two particularities that are of interest in this project: first, embryos are very big (approximately half a millimeter, 10 times bigger than a cell in the human body) and second, during the first 2 hours after fertilization, zebrafish embryos go through 10 rounds of synchronous mitotic divisions without growth. This means that cells become exponentially smaller in every division cycle. Therefore, in this project we asked the questions: how does cell division occur in an extremely big cell such as the 2 cell-stage zebrafish embryo? and which adaptation mechanisms the mitotic machinery uses to adjust to the fast decrease in cell size? Particularly in this project, we are focused on how chromosome segregation, the movement of replicated DNA into the two new daughter cells, is controlled in order to ensure equal distribution of the genetic material. During my PhD, I showed that cultured cells have a molecular mechanism based on the phosphorylation activity of the kinase Aurora B. The kinase activity creates a phosphorylation gradient between the two sets of chromosomes during anaphase and the phosphorylation/dephosphorylation balance of specific substrates regulates the distance of chromosome separation before nuclear envelop reformation (NER). Again, culture cells have approximately 20μm in diameter whereas the 2 cell-stage embryo is 10 bigger. Our objectives are: - Are the molecular mechanisms that control chromosome separation conserved in other systems? - How does this mechanism adapt to a 10 times bigger cell? - How does this mechanism changes with a fast decrease in cell size? So far, we observed that indeed the same phosphorylation activity exist in zebrafish embryos and controls the distance of chromosome separation before DNA decondensation. We have also observed that the mechanism adjusts to the decreasing cell size, essentially the phosphorylation activity of Aurora B scales with cell size. And finally, we observed that the scaling capacity is a function of changes in chromosome velocity for the different cell sizes. We are now addressing the question of how does the velocity of chromosome segregation scales with cell size.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз