Chromosomal and cytoplasmic context determines predisposition to maternal age-related aneuploidy: brief overview and update on MCAK in mammalian oocytes

Abstract

It has been known for more than half a century that the risk of conceiving a child with trisomy increases with advanced maternal age. However, the origin of the high susceptibility to nondisjunction of whole chromosomes and precocious separation of sister chromatids, leading to aneuploidy in aged oocytes and embryos derived from them, cannot be traced back to a single disturbance and mechanism. Instead, analysis of recombination patterns of meiotic chromosomes of spread oocytes from embryonal ovary, and of origins and exchange patterns of extra chromosomes in trisomies, as well as morphological and molecular studies of oocytes and somatic cells from young and aged females, show chromosome-specific risk patterns and cellular aberrations related to the chronological age of the female. In addition, analysis of the function of meiotic- and cell-cycle-regulating genes in oogenesis, and the study of the spindle and chromosomal status of maturing oocytes, suggest that several events contribute synergistically to errors in chromosome segregation in aged oocytes in a chromosome-specific fashion. For instance, loss of cohesion may differentially predispose chromosomes with distal or pericentromeric chiasmata to nondisjunction. Studies on expression in young and aged oocytes from human or model organisms, like the mouse, indicate that the presence and functionality/activity of gene products involved in cell-cycle regulation, spindle formation and organelle integrity may be altered in aged oocytes, thus contributing to a high risk of error in chromosome segregation in meiosis I and II. Genes that are often altered in aged mouse oocytes include MCAK (mitotic-centromere-associated protein), a microtubule depolymerase, and AURKB (Aurora kinase B), a protein of the chromosomal passenger complex that has many targets and can also phosphorylate and regulate MCAK localization and activity. Therefore we explored the role of MCAK in maturing mouse oocytes by immunofluorescence, overexpression of a MCAK-EGFP (enhanced green fluorescent protein) fusion protein, knockdown of MCAK by RNAi (RNA interference) and inhibition of AURKB. The observations suggest that MCAK is involved in spindle regulation, chromosome congression and cell-cycle control, and that reductions in mRNA and protein in a context of permissive SAC (spindle assembly checkpoint) predispose to aneuploidy. Failure to recruit MCAK to centromeres and low expression patterns, as well as disturbances in regulation of enzyme localization and activity, e.g. due to alterations in activity of AURKB, may therefore contribute to maternal age-related rises in aneuploidy in mammalian oocytes.

Oocyte ageing and its cellular basis

“…Oocytes contain large numbers of mitochondria but activity of mitochondria in meiotically arrested oocytes is comparatively low such that risks for oxidative damage by ROS are mimimal. Oocyte mitochondria contain few cristae, dense matrix and low inner membrane potential (reviewed by Eichenlaub-Ritter et al, 2010). Upon resumption of maturation a cortical domain of mitochondria with increased inner membrane potential is established upon loss of physical contacts between oocyte and cumulus.…”

“…Taken together with observations that obesity and diabetes increase spindle aberrations in young oocytes in mouse models (Wang et al, 2009), and that mice fed with moderately caloric restricted diet exhibit improved quality of aged oocytes and low aneuploidy rates (Selesniemi et al, 2010), all data point to a contributing role of alterations in follicular and oocyte metabolism and dysfunctional organelles in spindle aberrations and susceptibility to meiotic errors. In addition, mitochondria in aged human oocytes in resting primordial follicles and in follicle cells from stimulated cycles in ART are structurally and functionally altered (reviewed by Eichenlaub-Ritter et al, 2010). Depending on whether and to what extend such age-related alterations contribute to changes in follicular homeostasis, metabolism, altered expression patterns and loss of chromosome cohesion, it may become possible to prevent or delay these ageing events, e.g.…”

Age-related increase in aneuploidy and alteration of gene expression in mouse first polar bodies

“…APC-CDC20 is required for the onset of anaphase [26]. MCAK is involved in spindle regulation, chromosome congression and cell-cycle control, and that reduction in mRNA and protein in a context of permissive SAC predispose to aneuploidy [27]. Disruptions of either complex predispose oocyte to an increased incidence of aneuploidy [10,28].…”

Maternal control of oocyte quality in cattle “a review”

“…There is sufficient evidence that with advanced age mitochondrial pathophysiology contributes to decreased female fertility, such as: (1) occurrence of spindle aberrations attributed to insufficient energy supply, and/or shifts in redox regulation, might influence enzyme activities and cause loss of chromosome cohesion, or chromosome integrity and stability, especially during early embryogenesis (Cukurcam et al, 2007;Eichenlaub-Ritter et al, 2010), (2) increase in the rate of DNA mutations in oocyte mitochondria (Keefe et al, 1995), (3) decrease in mitochondrial metabolic activity , (4) inefficiency in mitochondrial ATP production (Van Blerkom et al, 1995), (5) changes in mitochondrial calcium homeostasis (Van Blerkom, 2011).…”