Molecular causes of aneuploidy in mammalian eggs

Abstract

SummaryMammalian oocytes are particularly error prone in segregating their chromosomes during their two meiotic divisions. This results in the creation of an embryo that has inherited the wrong number of chromosomes: it is aneuploid. The incidence of aneuploidy rises significantly with maternal age and so there is much interest in understanding this association and the underlying causes of aneuploidy. The spindle assembly checkpoint, a surveillance mechanism that operates in all cells to prevent chromosome mis-segregation, and the cohesive ties that hold those chromosomes together, have thus both been the subject of intensive investigation in oocytes. It is possible that a lowered sensitivity of the spindle assembly checkpoint to certain types of chromosome attachment error may endow oocytes with an innate susceptibility to aneuploidy, which is made worse by an age-related loss in the factors that hold the chromosomes together.

Reduced ability to recover from spindle disruption and loss of kinetochore spindle assembly checkpoint proteins in oocytes from aged mice

“…41 In principle, a reduction in either Mad2 or pAurora C, could influence the fidelity of bivalent segregation at the end of MI. This is supported by the observations that when individual SAC proteins are reduced or knocked-out in oocytes, rates of aneuploidy in the resulting eggs are raised, 1,15,17,42 and when young oocytes are cultured with the Aurora kinase inhibitor ZM447439, a significant reduction in kinetochore pAurora C (Fig. S2A) and a rise in aneuploidy at MI completion are both measured (Fig.…”

“…Reduced SAC with maternal age A functional SAC is essential for faithful chromosome segregation in both mitosis and meiosis, 12,13 and interruption of SAC components in mouse oocytes, such as Mad2 or Aurora C, accelerates meiotic progression and increases aneuploidy rates. 1,15 In fact we have recently observed that SAC proteins have functions that last the entire period of MI, not just the canonical period of prometaphase, and are essential in slowing down the time taken to complete MI-a phenomenon that promotes bivalent biorientation and reduces mis-segregation. 66 However, whether a defective SAC is involved in aged mouse oocytes remains elusive.…”

“…[1][2][3] It is primarily brought about by the missegregation of chromosomes during the 2 meiotic divisions of the oocyte (meiosis I, MI; meiosis II, MII), and advanced maternal age is an important risk factor. The leading hypothesis to account for the maternal age effect, based on studies in mice that replicate this phenomenon, posits that aneuploidy is derived from chromosome cohesion loss during the long period of prophase I arrest, which is unique to mammalian oocytes and precedes the first of the 2 meiotic divisions.…”

“…The SAC is certainly active in mouse oocytes, as its loss can raise aneuploidy rates considerably. 1,[15][16][17][18] However, the SAC is not as stringent in mouse oocytes as it is in somatic cells, [19][20][21][22][23] and in human and mouse oocytes, aging is associated with a reduction in levels of SAC components such as Mad2. [24][25][26][27] Although these data offer credence for a SAC basis to the maternal aging phenomenon, there are other studies demonstrating the SAC is active in aged oocytes.…”

A putative role for anti-Müllerian hormone (AMH) in optimising ovarian reserve expenditure

“…During embryonic development, primordial germ cells migrate from the primitive streak through the endoderm to the genital ridge where they differentiate into oogonia while the foetal ovary forms (Richardson & Lehmann 2010). After the initial burst of oogonial proliferation, the cells begin meiosis, but the process is arrested in prophase-I (Jones & Lane 2013). The arrested oocytes initially form clusters and then become encapsulated in pre-granulosa cells, forming a structure known as the primordial follicle, which represents a dormant, non-growing state (Kerr et al 2013).…”