Low nucleus to cytoplasmic ratio compromises cytokinesis, genome stability and development in haploid embryonic cells

Authors:
  • DGDaniela Georgieva
    Daniela Georgieva
  • SXShuangyi Xu
    Shuangyi Xu
  • MDMatthew Dennen
    Matthew Dennen
  • QDQian Du
    Qian Du
  • GCGloryn Chia
    Gloryn Chia
  • SASelma Amrane
    Selma Amrane
  • LGLisa C. Grossman
    Lisa C. Grossman
  • AAAlejandro De Los Angeles
    Alejandro De Los Angeles
  • RPRobert Prosser
    Robert Prosser
  • RLRogerio Lobo
    Rogerio Lobo
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Abstract
Mammalian species exist as diploid organisms, with only gametes existing as stable, nonproliferating haploids. Haploid mammalian pluripotent stem cells, in all derived species to date - mouse, human and rat - undergo spontaneous diploidization. Here, we investigated the mechanisms affecting the stability of the haploid state using the mouse and human embryo, as well as a human embryonic stem cells. We demonstrate that diploidization occurs early in preimplantation development and is often unproductive, with haploid embryos exhibiting decreased developmental potential. Haploid embryos show increased chromosome segregation errors at the first mitosis, failure to align chromosomes on the metaphase plate in the second mitosis. Delayed mitotic progression and failure to form a central spindle and a midbody are followed by cytokinesis failure, diploidization, increased DNA damage marked by γH2AX and RPA32 foci, and low developmental potential. By increasing the nucleo-cytoplasmic ratio in diploids, or reducing this ratio in haploids, these phenotypes can be induced in diploids or reduced in haploids. Changing ploidy alone from haploid to diploid without also adjusting nucleo-cytoplasmic ratio does not improve mitotic phenotypes and developmental outcomes. Thus, the most upstream driver responsible for the instability of the haploid state is a stage- specific ratio of nucleus to cell size.

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