Biology subjects

McAinsh, A.

Publications and source records attributed to McAinsh, A..

4 recordsLinked to original sources

bioRxiv2025

Attenuation of mosaic aneuploidy and erroneous first mitotic division of human embryos

Human reproduction is inherently inefficient1 and 1 in 6 people worldwide suffer infertility. In vitro fertilisation (IVF) can help some couples conceive, but only ~30% of cycles are successful. One factor affecting IVF efficacy is mitotic-origin (mosaic) aneuploidy in which embryos contain a mixture of cells with different numbers of chromosomes2. We previously showed that chromosome segregation error phenotypes are frequent in the first mitotic division of the human embryo3. However, the cause of these errors and impact on daughter cell karyotype is unknown. Here, using live chromosome imaging and next generation sequencing we show that activation of the microtubule depolymerase KIF2C reduces chromosome segregation errors and mitotic-origin aneuploidy at the 2-cell stage. The number of first divisions that show alternative cleavage patterns (associated with failed embryo development in IVF clinics) are also reduced with KIF2C activation. Our findings demonstrate that modulation of microtubule dynamics is a potential therapeutic route to improving human embryo quality and IVF outcomes.

cell biology↗

bioRxiv2024

The Chromosome Periphery is an Essential Compartment of Oocyte Chromosomes

Chromosomes and their constituent compartments are core elements of the cell division machinery. In mammalian oocytes, defects in the structure or composition of chromosomes are a leading cause of aberrant or failed meiosis, and by extension, can cause miscarriage and infertility. The underlying mechanisms are poorly understood, but are critical for development of novel diagnostics and treatments. The chromosome periphery, the least understood chromosome compartment, has recently emerged as an essential component of mitotic chromosomes and somatic cell division. However, in female meiosis it remains completely unexplored. This study provides the first comprehensive survey of a meiotic chromosome periphery compartment in both human and mouse oocytes. Using a combination of time-lapse microscopy, super-resolution imaging and 3DCLEM we show that removing the chromosome periphery, via Ki67 depletion, has substantial negative impact on chromosome structure, spatial organization and positional awareness, with many oocytes stalling and arresting in meiosis I. Importantly, we also reveal key differences between the mitotic and oocyte meiotic chromosome periphery compartments, most remarkably in the retention of Ki67 in the oocyte through anaphase I, where unwanted chromosomes are stripped of Ki67 before being ejected from the oocyte. This work presents the discovery of an exciting new pathway operating during female meiosis and a provides a platform for future work exploring the meiotic chromosome periphery for therapeutic vulnerabilities.

cell biology↗

bioRxiv2021

Computational modelling and near-complete kinetochore tracking reveal how chromosome dynamics during cell division are co-ordinated in space and time

Mitotic chromosome segregation is a self-organising process that achieves high fidelity separation of 46 duplicated chromosomes into two daughter cells. Chromosomes must be captured by the microtubule-based spindle, aligned at the spindle equator where they undergo oscillatory motion (metaphase) and then pulled to opposite spindle poles (anaphase). These large and small-scale chromosome movements are driven by kinetochores, multi-protein machines, that link chromosomes to microtubules and generate directional forces. Through automated near-complete tracking of kinetochores at fine spatio-temporal resolution over long timescales, we produce a detailed atlas of kinetochore dynamics throughout metaphase and anaphase in human cells. We develop a hierarchical biophysical model of kinetochore dynamics and fit this model to 4D lattice light sheet experimental data using Bayesian inference. We demonstrate that location in the metaphase plate is the largest factor in the variation in kinetochore dynamics, exceeding the variation between cells, whilst within the spindle there is local spatio-temporal coordination between neighbouring kinetochores of directional switching events, kinetochore-fibre (K-fibre) polymerization/depolymerization state and the segregation of chromosomes. Thus, metaphase oscillations are robust to variation in the mechanical forces throughout the spindle, whilst the spindle environment couples kinetochore dynamics across the plate. Our methods provide a framework for detailed quantification of chromosome dynamics during mitosis in human cells.

cell biology↗

bioRxiv2019

CENP-F controls force generation and the dynein-dependent stripping of CENP-E at kinetochores

Accurate chromosome segregation demands efficient capture of microtubules by kinetochores and their conversion to stable bi-oriented attachments that can congress and then segregate chromosomes. An early event is the shedding of the outermost fibrous corona layer of the kinetochore following microtubule attachment. Centromere protein F (CENP-F) is part of the corona, contains two microtubule-binding domains and physically associates with dynein motor regulators. Here, we have combined CRISPR gene editing and engineered separation-of-function mutants to define how CENP-F contributes to kinetochore function. We show here that the two microtubule-binding domains make distinct contributions to attachment stability and force generation that are required to minimise errors in anaphase, but are dispensable for congression. We further identify a specialised domain that functions to inhibit the dynein mediated stripping of CENP-E motors. We show how this \"dynein-brake\" is crucial for ensuring kinetochores contain the right number of CENP-E motors at the right time during mitosis, with loss of brake function delaying congression.

cell biology↗