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The aging germ cell – biological pathways, risk factors and mechanisms underlying an increasing medical and socio-economic problem

Periodic Reporting for period 4 - GermAge (The aging germ cell – biological pathways, risk factors and mechanisms underlying anincreasing medical and socio-economic problem)

Période du rapport: 2019-11-01 au 2020-10-31

The objective of GermAge is to understand the drastic and medically very concerning decline in germ cell quality during aging. The aging population and the dramatically increasing age of parenthood are associated with severe medical problems, declining reproductive health, and substantial consequences for the socio-economic well-being of our societies. Therefore there is an urgent need to understand the biological basis and to identify risk factors and pathways of the steep age-dependent decline in female and male germ cell quality. Thus, the objective is to define the determinants, pathways and risk factors for age-dependent infertility, aneuploidy and inherited diseases. The aims include the understanding of the biological basis for the dramatic age-dependent decline in fertility and the increase in chromosome mis-segregation syndromes. Risk factors and potentially biomarkers, are to be defined to improve future diagnostics and to set the stage for future therapeutic or preventive intervention strategies. An extensive effort in basic research is required to make achieving these aims possible. GermAge therefore strived to very substantially contribute to reaching this goal and has generated key data enhancing our understanding of this key problem of human reproductive health.
The objectives of GermAge were largely achieved. We have identified and characterized germ cell pathways that are key to germ cell quality during ageing such as cohesins and cohesion regulatory factors and newly described factors. A number of biological mechanisms were identified and characterized and new factors involved in germ cell ageing and associated problems described. The mouse deficiency model of one newly identified factor, CENP-V, serves as a new model for the weakening of a key surveillance mechanism (the SAC) that ought to prevent chromosome mis-segregation in ageing germ cells, but over time fails to do so. Cohesins, which keep chromosomes properly structured and ordered in dividing germ cells, deteriorate in ageing oocytes, which leads to chromosome miss-segregation as well. Thus, mechanisms that support cohesive cohesin and that protect cohesin from removal were studied and found to be highly important in avoiding meiotic errors. RNA-modifying and monitoring factors acting in male germ cells were characterized and found critical for gametogenesis. Spermatogonial age-dependent and regeneration-related changes in gene expression patterns were determined. For meiosis II, two processes were found by GermAge to contribute to age-dependent aneuploidy: error-prone kinetochore-microtubule attachment and reduced efficiency of the process that corrects aberrant kinetochore-microtubule attachments. Within GermAge these processes and the respective control mechanisms were studied. Damage at the chromosome ends, the telomeres, was found to also happen when cohesins disappear and likely contributes to germ cells failures. Thus, new pathways and risk factors were identified which will likely be important for improving reproductive health, e.g. they may well develop into diagnostic markers in human reproductive medicine, such as in IVF settings. In addition, innovative technologies were developed and established that will substantially help this research field to move forward. Molecular and cell biology tools, new sophisticated animal models, and novel imaging approaches were developed, sometimes in combination with bioinformatics processes. Among these are imaging technologies such as live cell 3D chromosome tracking, super-resolution live cell oocyte imaging, and Cas9-mediated labeling of chromosomal loci in oocytes, as well as barcoding of germ cell populations for fate-tracking, and the use of novel fluorescent dyes that specifically label relevant structures such as microtubuli in oocytes. These and other are now available to the scientific community and expected to have a major impact on the progress of germ cell research.
"The four-member GermAge consortium has published a considerable number of scientific papers, which attracted substantial attention in the scientific community, as is evidenced also by numerous presentations that GermAge members delivered at scientific conferences. The scientific papers include publications in top journals such as in Nature, J Cell Biol, Nature Comm, Nature Struct Mol Biol, Current Biol, EMBO-Journal. So 20 papers were published or are to be published shortly as a result of the GermAge program.

Through a number of public articles, interviews and presentations at lay events, GermAge has also raised public awareness of the risks associated with postponing parenthood. As this is a growing problem of societies in the industrialized countries, education of the general public and of decision-makers is very important. For an example, most recently Prof Herbert did an interview BBC radio 4 ""Woman's Hour"" on egg freezing and female reproductive ageing. The estimated audience for this programme is 3.7 million listeners weekly and is the second most popular daily podcast across BBC Radio.

In figure1 from the Herbert lab, the microtubule-associated protein, newly described for its role in oocytes, is seen stained in green in human oocytes at different stages of their maturation (GVBD = germinal vesicle breakdown; PBE = polar body extrusion; chromosomes in blue, centromeres in red). These images show the dynamic localization of PRC1, which as observed within the GermAge project encapsulates chromosomes during exit from metaphase I.

The second figure (Jessberger lab) displays chromosomes and spindle in mouse oocytes that are proficient (top row) or deficient (lower row) for the protein CENP-V, also first described within the GermAge project. In absence of CENP-V some chromosomes, like the one indicated by an arrow, fail to align on the metaphase plate. This can lead to chromosome mis-segregation, which is observed in this mutant (Tubilin, red), centromeres, green; chromosomes, blue)."