Maturation Failures and Oocyte Aging

Maturation failures and oocyte aging share common features to some extent in that absence of meiotic spindle formation (maturation failures) or defective meiotic spindles (maturation failures and oocyte aging) are associated with both. Both have been studied in several animal models and to a lesser extent in humans, yielding some although incomplete information on maturation failures and oocyte aging. Excellent data are available on mechanisms underlying chromosome mis-segregation and aneuploidy in aging oocytes (reviewed by Jones, 2008; Holt and Jones, 2009; Wang et al., 2011; Qiao et al., 2014), resulting in various syndromes such as Down’s syndrome (trisomy 21), Edwards syndrome (trisomy 18), Patau syndrome (trisomy 13), Turner’s syndrome (monosomy x), Triple-X syndrome (trisomy X), and Klinefelter’s syndrome (47 XXY). Several studies have been undertaken to reveal possible causative mechanisms underlying chromosome mis-segregation in aging oocytes with focus on failure in connections between microtubules and kinetochores (reviewed in Qiao et al., 2014) using model organisms (Gluszek et al., 2015) and human (Zielinska et al., 2015) oocytes.

We also know that microtubules and centrosomes become unstable in aging oocytes but we only have sporadic information on the sequence of events leading to oocyte aging (reviewed in Schatten and Sun 2011a,b, 2013, 2015a; Miao et al., 2009a,b; Wang et al., 2011; Qiao et al., 2014; Prasad et al., 2015). Based on morphological and molecular analyses we also know that oocyte aging includes changes in calcium metabolism, loss of cortical granule functions, destabilization of the cytoplasmic microfilament and microtubule cytoskeleton, decrease in essential organelle functions with significant loss in mitochondrial functions and decrease in ATP. Many of these alterations may be interrelated and consequential once one specific initiating event has taken place; alternatively, several events may occur simultaneously.

For NuMA, we have shown that absence or reduced immunos- taining of NuMA at the meiotic poles is associated with maturation failures and oocyte aging. Similar to results reported for у-tubulin

(George et al., 1996) ectopic localization of NuMA in the ooplasm is associated with oocyte aging. Small asters containing NuMA focal points are detected in aging human oocytes (Alvarez-Sedo et al., 2011). We showed that minus end-directed dynein motor activities play a role in NuMA transport to the meiotic poles and that this transport is likely to be affected in aging oocytes. Microtubule motor activities depend on accurate microtubule dynamics, which involves posttranslational modifications (PTMs) of microtubules (reviewed in Schatten and Sun 2014, 2015a,b). We had previously shown that microtubule acetylation is lost or decreased in aging oocytes (Schatten et al., 1988) which affects microtubule stability as well as association of microtubule motor proteins with microtubules (reviewed in Schatten and Sun 2014, 2015a,b), thereby affecting accurate transport of centrosomal proteins such as NuMA along microtubules.

During oocyte aging, a significant loss of centrosome integrity occurs that includes dispersion of proteins from the centrosome core structure, and loss of attachment of microtubules to centrosomes and kinetochores. The dispersion of у-tubulin (George et al., 1996) and NuMA (Alvarez-Sedo et al., 2011) from the centrosome core structure resulting in numerous small у-tubulin and NuMA aggregates in the ooplasm of aging human oocytes has been well documented. These cytoplasmic asters resulting from oocyte aging are atypical for non-rodent mammalian oocytes and different from the cytasters in non-aging mouse oocytes, as in the mouse cytasters are part of the mechanisms employed to form the MII spindle (Schatten et al., 1985, 1988; Maro et al., 1985). Interestingly, the cytoplasmic asters typical for young mouse oocytes disintegrate in the mouse during oocyte aging (Miao et al., 2009a). These significant differences are important for studies on aging to avoid misinterpretations.

Failure in MII spindle function can lead to aneuploidy and consequences for embryo development with developmental abnormalities resulting in abortion, disease, or developmental defects (reviewed in Miao et al., 2009a,b; Wang et al., 2011; Schatten and Sun 2013; Qiao et al., 2014). Oocyte aneuploidies may play a role in childhood or adolescent diseases including childhood cancer with characteristic centrosome dysfunctions that may have originated from abnormal oocyte centrosomes; centrosome abnormalities are hallmarks of cancer (Schatten et al., 2000; Schatten 2008).

Understanding the defects occurring in fertilization-compromised oocytes will help us design therapies to overcome the specific identified defects. For example, several compounds have been identified to restore spindle integrity in aging oocytes in which the MII spindle had become deteriorated. Kikuchi et al., (2000, 2002) found that caffeine delays or prevents oocyte aging (reviewed in Miao et al., 2009a) by controlling the activity of MPF. As mentioned previously, both MPF and MAPK are important for maintaining MII spindle integrity and that decreased MPF and MAPK activity leads to MII spindle integrity loss (Xu et al., 1997; Tian et al., 2002; Fan and Sun, 2004; Tatone et al., 2006; Liang et al., 2007; Lee and Campbell, 2008). Others have used nitric oxide (NO; Goud et al., 2005a,b), dithiothreitol (DTT; Rausell et al., 2007; Tarin et al., 1998), and trichostatin A (TSA; Jeseta et al., 2008; Huang et al., 2007) to delay or reverse oocyte aging (reviewed in more detail in Schatten and Sun 2015a,b). Future approaches may include newly developed inhibitors of microtubule deacetylation (Butler et al., 2010) to prevent deacetylation of microtubules in meiotic spindles, thereby stabilizing the meiotic spindle and maintaining spindle integrity (reviewed in detail in Schatten and Sun 2015a). It is also worth mentioning that aside from physiological maturation failures and oocyte aging environmental factors can cause abnormal MI and MII spindle formation (reviewed in detail in Schatten and Sun 2009a,b).

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