Report
Teaser, summary, work performed and final results
Periodic Reporting for period 2 - COREMA (Cell division and the origin of embryonic aneuploidy in preimplantation mouse development)
Teaser
Cell division is fundamental for the early development of the mammalian embryo. It drives the rapid early proliferation of totipotent cells and formation of a multicellular organism. Strikingly, the reported incidence of chromosome aberrations in early human embryos exceeds...
Summary
Cell division is fundamental for the early development of the mammalian embryo. It drives the rapid early proliferation of totipotent cells and formation of a multicellular organism. Strikingly, the reported incidence of chromosome aberrations in early human embryos exceeds 50% and hence is a major cause of infertility and congenital diseases. Why aneuploidy (presence of an abnormal number of chromosomes in a cell) is so prevalent at the beginning of mammalian life and how development nevertheless achieves robustness is fundamentally not understood. The overall goal of the proposed research is to characterise the cell divisions of the mouse embryo occurring before the embryo implants into the uterus of its mother in order to mechanistically understand which errors in cell division processes cause aneuploidy and what the consequences for early development are. Enabled by new imaging technology development for live embryo imaging, we will map when, how and why cell division goes awry, identify the key mitotic pathways that underlie aneuploidy generation, and dissect the responsible molecular mechanism(s).
Work performed
While we continue to develop new imaging technology to be able to look into the developing embryo even in more details and characterise the cell biological processes underlying aneuploidy generation, the first intriguing results of our work on early mouse embryos have now been published (Reichmann, J. et al. Dual spindle formation in zygotes keeps parental genomes apart in early mammalian embryos. Science, published online 12 July 2018.). Fusion of egg and sperm combines the genetic material of both parents in one cell. In mammals including humans, each parental genome is initially confined in a separate pronucleus. For the new organism to develop, the two genomes have to be spatially coordinated so that the first embryonic division can create two cells that combine both genomes in one nucleus. We could show that at the beginning of the first division, two microtubule spindles organise the maternal and paternal chromosomes and subsequently align to segregate the parental chromosomes in parallel. Failure of spindle alignment leads to two-celled embryos with more than two nuclei. Dual spindle assembly in the zygote thus offers a potential mechanistic explanation for division errors frequently observed in human embryos in the fertility clinic.
This discovery of the existence of the dual spindle resulted in a broad media coverage across the world and interest by the general public. The impact of this work was highlighted in several German newspapers and magazines (FAZ, Zeit, Süddeutsche, Spektrum der Wissenschaft and EMMA) as well as by a Science perspective article written by Melina Schuh, a Developmental Cell preview article by Michael A. Lampson and a Dispatch in Current Biology article by Marie-Hélène Verlhac. The relevance of our findings for reproductive medicine is furthermore reflected by its influence on ethical discussions especially in Germany. In this context Reichmann et al. was cited in the Leopoldina (German Academy of Science) recommendation for a new law for reproductive medicine presented to the German government in June 2019.
Final results
The new imaging technologies developed in our lab allow for the first time detailed insights into the processes occurring in the developing embryo. During the course of the project, we expect more surprising discoveries, similar to the discovery of the dual-spindle, as the spatio-temporal resolution of the in-house developed microscopes is unprecedented.