Upstream eventDisorganization, Spindle
Altered, Meiotic chromosome dynamics
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Chemical binding to tubulin in oocytes leading to aneuploid offspring||adjacent||Moderate|
Life Stage Applicability
Key Event Relationship Description
Incorrect spindle organization refers to lack of the bipolar organization of the spindle within the cell. This bipolar organization is required to assure that chromosomes will align correctly to the metaphase plate prior to equal division between the daughter cells. Alternatively, incorrect spindle formation can lead to shorter spindle fibers and/or incorrect length of these fibers, which leads to chromosome misalignment.
In this KER, chemicals that cause spindle disorganization lead to altered meiotic chromosome dynamics. The relationship between spindle disorganization and altered chromosome dynamics can occur in both somatic and in germ cells; however, this relationship focuses on female meiotic chromosomes because of the differences in how the meiotic spindle is assembled in oocytes with respect to other cell types (i.e., lack of centrioles and dependency on microtubule organizing centers). Interestingly, some studies investigating the effects of protein deficiencies in mouse oocytes provide direct evidence of the events involved in the KER [McGuinnes et al., 2009; Ou et al., 2010; Baumann et al., 2017]. For example, targeting deletion of Bub1 in mouse oocytes caused dysregulation of spindle assembly and leads to defective chromosome congression [McGuinness et al., 2009]. After depletion of p38a in mouse oocytes, a MTCO component, aberrant spindle organization, including defective or multipolar spindles are more than 3 times more frequent than in control mice, while there is an 8-fold increase in chromosome congression defects [Ou et al., 2010]. Finally, in a study carried out using an oocyte conditional pericentrin knockout mouse model and live cell imaging, alterations in spindle size have been observed, together with delay in meiotic spindle formation following in vitro culture of cumulus-enclosed oocytes. These abnormalities were associated with a significant increase in the number of unattached kinetochores and merotelic attachments, as well as, an increase in misaligned and uncongressed chromosomes [Baumann et al., 2017].
Evidence Supporting this KER
Moderate, based on strong biological plausibility and weak emprical evidence.
The weight of evidence for this KER is moderate. It is well understood that the proper organization of the meiotic spindle is necessary in order for chromosomes to correctly align. This process has been extensively described in the literature. For a recent comprehensive review on this topic, please see Bennabi et al. .
Although it is very common to measure spindle abnormalities (i.e., spindle disorganization), few studies have examined meiotic chromosome dynamics. Thus, there are insufficient empirical data examining the concordance between spindle abnormalities and chromosome dynamics.
However, two in vitro studies on mouse eggs have investigated spindle abnormalities and chromosome congression defects within individual studies (i.e., both endpoints measured). These studies used nocodazole and 2-methoxyestradiol to demonstrate that there is a temporal and dose-response related consistency among the events; i.e., downstream KEs are occurring at higher doses and later time points than upstream KEs [Shen et al., 2005; Eichenlaub-Ritter et al., 2007]. Further evidence supporting this KER has been collected in somatic cells, especially in vitro (reviewed in Silkworth and Cimini, 2012)
Uncertainties and Inconsistencies
There is not extensive empirical data this KER, however, the available data does not show inconsistencies.
Quantitative Understanding of the Linkage
Although there are no inconsistent results reported, it is important to note that very few studies have measured chromosome dynamics in oocytes in general. Thus, there is a large amount of uncertainty surrounding the qualitative and quantitative association between these two endpoints.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Although this KER has only been measured in mouse oocytes, the process of meiosis, spindle formation and chromosome congression in eggs is thought to be similar across mammalian species.
Baumann C, Wang X, Yang L, Viveiros MM. 2017. Error-prone meiotic division and subfertility in mice with oocyte-conditional knockdown of pericentrin. J Cell Sci 130:1251-1262.
Eichenlaub-Ritter U, Winterscheidt U, Vogt E, Shen Y, Tinneberg HR, Sorensen R. 2007. 2-methoxyestradiol induces spindle aberrations, chromosome congression failure, and nondisjunction in mouse oocytes. Biol Reprod 76:784–793.
McGuinness BE, Anger M, Kouznetsova A, Gil-Bernabe AM, Helmhart W, Kudo NR, Wuensche A, Taylor S, Hoog C, Novak B, Nasmyth K. 2009. Regulation of APC/C activity in oocytes by a Bub1-dependent spindle assembly checkpoint. Curr Biol 19:369-380.
Ou XH, Li S, Xu BZ, Wang ZB, Quan S, Li M, Zhang QH, Ouyang YC, Schatten H, Xing FQ, Sun QY. 2010. p38alpha MAPK is a MTOC-associated protein regulating spindle assembly, spindle length and accurate chromosome segregation during mouse oocyte meiotic maturation. Cell Cycle 9:4130-4143
Shen Y, Betzendahl I, Sun F, Tinneberg HR, Eichenlaub-Ritter U. 2005. Non-invasive method to assess genotoxicity of nocodazole interfering with spindle formation in mammalian oocytes. Reprod Toxicol 19:459–471.
Silkworth WT, Cimini D. 2012. Transient defects of mitotic spindle geometry and chromosome segregation errors. Cell Div 7:19.