To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:715

Relationship: 715

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Disruption, Microtubule dynamics leads to Disorganization, Meiotic Spindle

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Chemical binding to tubulin in oocytes leading to aneuploid offspring adjacent Moderate Francesco Marchetti (send email) Open for citation & comment EAGMST Under Review

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens Moderate NCBI
mouse Mus musculus Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Adult High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Spindle organization and function requires normal microtubule dynamics. When microtubule polymerization is affected (i.e., depolymerization), spindle organization and function is impaired.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Moderate.

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

The weight of evidence for this KER is moderate. Microtubule polymerization is critical for the appropriate functioning of the spindle. Mitotic and meiotic spindles differ in how they are assembled. In mitotic cells, spindle organization is controlled by centrioles [Walczak and Heald, 2008; Wadsworth et al., 2011; Wittman et al., 2011]. However, centrioles are absent in mammalian oocytes [Manandhar et al., 2005] and meiotic spindle is organized by multiple microtubule organizing centers (MTOCs). Gradually, MTOCs coalesce and surround the chromosomes and subsequently elongate in a typical barrel-shape bipolar spindle [Schuh and Ellenberg, 2007; Clift and Schuh, 2015], similar to the mitotic spindle. Assembly, elongation and function of the spindle requires proper microtubule dynamics. If microtubules become depolymerized, it affects the structural integrity of the spindle resulting in abnormal spindles that are characterized by reduction in microtubule density, loss of barrel shape, mono- or multi-polar spindle, and reduced distance between the poles [Ibanez et al., 2003; Shen et al., 2005; Eichenlaub-Ritter et al., 2007; Xu et al., 2012]. The normal biology underlying the critical role of proper microtubule polymerization for the appropriate structure and function of spindle is well established, and it is widely understood that chemicals that alter microtubule dynamics cause spindle disorganization [Manandhar et al., 2005; Schuh and Ellenberg, 2007].

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

There are not a lot of studies that have explored these two events within the same experiment. Thus, the empirical evidence is not based on a large number of papers. However, the papers that are available are of sound experimental design that address both time and incidence relationships, and span three species.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Due to the heterogeneity of the experimental approaches used to measure dysruption of microtubule dynamics (KEupstream) and spindle disorganization (KEdownstream) it is not feasible to identify modulating factors acting in this KER.

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

There are detailed dose-response relationships for microtubule depolymerisation by tubulin binders obtained using acellular tubulin polymerization assays [Zavala et al., 1980; Hamel and Lin, 1981; Verdier-Pinard et al., 1998; Miller and Wilson, 2010]. The rate of depolymerisation has been also measured in whole mitotic cells of sea urchin embryos after microinjection of different doses of colchicine or colcemid, in the range 0.01-5 mM [Salmon et al., 1984]. Comparable data are not available for mammalian oocytes. In addition, no quantitative dose-response relationship has been obtained for spindle disorganization in oocytes treated with tubulin binding chemicals. This lack of data does not allow modelling a response-response relationship between disruption of microtubule dynamics (KEupstream) and spindle disorganization (KEdownstream).

Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

In sea urchin embryo cells microinjected with colchicine concentrations equal to or higher than 0.1 mM, complete depolymerization of non-kinetochore spindle microtubules (KEupstream) is reached in about 20 seconds, corresponding to a depolymerization rate of about 180-992 dimers per second [Salmon et al., 1984]. The order of magnitude of these values corresponds to the fastest rates of tubulin dissociation reported in various acellular systems [Fan’ell et al., 1983]. However, possible modifying factors of the above rates are suggested in the cells (e.g., calcium concentration), conditions that are not reproducible in acellular systems.

In vitro exposure of mouse oocytes to 67 µM nocodazole causes a gradual disorganization of the spindle (KEdownstream), which is completed within 15 min [Xu et al., 2012]. In spite of the limited amount of data on the kinetics of spindle disorganization (KEdownstream) and the further limitation that dysruption of microtubule dynamics (KEupstream) and spindle disorganization (KEdownstream) were not analyzed in the same biological systems, it can be noted that the time-scale in the KEdownstream is coherent with the time-scale of the KEupstream.

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

To our knowledge, there are no feedback loops influencing this KER.

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Data were produced in sea urchins, mice and human eggs and embryos. This KER should be applicable to any eukaryotic organism.

References

List of the literature that was cited for this KER description. More help

Clift D, Schuh M. 2015. A three-step MTOC fragmentation mechanism facilitate bipolar spindle assembly in mouse oocytes. Nat Commun 6:7217.

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.

Fan'ell KW, Himes RH, Jordon MA,Wilson L. 1983. On the nonlinear relationship between the initial rates of dilution induced microtubule disassembly and the initial free subunit concentration. J Biol Chem 258:14148-14156.

Hamel E, Lin CM. 1981. Stabilization of the colchicine-binding activity of tubulin by organic acids. Biochim Biophys Acta 675:226-231.

Ibanez E, Albertini DF, Overstrom EW. 2003. Demecolcine-induced oocyte enucleation for somatic cell cloning: Coordination between cell-cycle egress, kinetics of cortical cytoskeletal interactions, and second polar body extrusion. Biol Reprod 68:1249–1258.

Liu S, Li Y, Feng HL, Yan JH, Li M, Ma SY, Chen ZJ. 2010. Dynamic modulation of cytoskeleton during in vitro maturation in human oocytes. Am J Obstet Gynecol 151:e1–7.

Manandhar G, Schatten H, Sutovsky P. 2005. Centrosome reduction during gametogenesis and its significance. Biol Reprod 72:2-13.

Miller HP, Wilson L. 2010. Chapter 1 - Preparation of Microtubule Protein and Purified Tubulin from Bovine Brain by Cycles of Assembly and Disassembly and Phosphocellulose Chromatography. In: Leslie W, John JC, editors. Methods Cell Biol: Academic Press. p 2-15.

Salmon ED, McKeel M, Hays T. 1984. Rapid rate of tubulin dissociation from microtubules in the mitotic spindle in vivo measured by blocking polymerization with colchicine. J Cell Biol 99:1066-1075.

Schuh M, Ellenberg J. 2007. Self-organization of MTOCs replaces centrosome function during acentrosomal spindle assembly in live mouse oocytes. Cell 130:484-498.

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.

Verdier-Pinard P, Lai JY, Yoo HD, Yu J, Marquez B, Nagle DG, Nambu M, White JD, Falck JR, Gerwick WH, Day PW, Hamel E. 1998. Structure-activity analysis of the interaction of curacin A, the potent colchicine site antimitotic agent, with tubulin and effects of analogs on the growth of MCF-7 breast cancer cells. Mol Pharmacol 53:62-76.

Wadsworth P, Lee WL, Murata T, Baskin TI. 2011. Variations on a theme: spindle assembly in diverse cells. Protoplasma 248:439-446.

Walczak CE and R Heald. 2008. Mechanisms of mitotic spindle assembly and function. Int. Rev Cytol 265:111-158.

Wittman T, Hyman A, Desai A. 2011. The spindle: a dynamic assembly of microtubules and motors. Nat Cell Biol 3:e28-234.

Xu XL, Ma W, Zhu YB, Wang C, Wang BY, An N, An L, Liu Y, Wu ZH, Tian JH. 2012. The microtubule-associated protein ASPM regulates spindle assembly and meiotic progression in mouse oocytes. PLoS One 7:e49303.

Zavala F, Guenard D, Robin JP, Brown E. 1980. Structure--antitubulin activity relationship in steganacin congeners and analogues. Inhibition of tubulin polymerization in vitro by (+/-)-isodeoxypodophyllotoxin. J Med Chem 23:546-549.