H2020Индивидуална стипендия2021–2023

DualSpindleAssembly · Defining the mechanism of the dual spindle assembly and alignment in the mammalian zygote

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2021-06-01 → 2023-05-31
Финансиране от ЕС: 174 806 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Механизмът на формиране и подравняване на двете вретена, които разпределят майчините и бащините хромозоми в зиготата, е обект на анализ. Разбирането на този процес помага да се обяснят причините за неправилното делене на клетките, безплодието и вродените нарушения.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Defining the mechanism of the dual spindle assembly and alignment in the mammalian zygote

The development of mammalian life begins with fertilization, the fusion of two haploid cells, oocyte and sperm, which results in the formation of the diploid zygote containing two pronuclei. For the faithful development of an organism, maintenance of its genomic integrity during early embryonic mitosis is essential as genetic abnormalities transmitted through the blastomeres can result in pregnancy failures and/or severe fetal disorders. Given its crucial importance, cell division is surprisingly error-prone at the beginning of mammalian life. The reported incidence of aneuploidy (presence of an abnormal number of chromosomes in a cell) in early human embryo exceeds 50% and is a major cause of infertility and severe congenital disorders. The first embryonic division is of particular importance as it facilitates the union of the maternal and paternal genomes. In the past it has been thought that a single spindle combines the maternal and paternal chromosomes. However, it is recently shown that two bipolar spindles form in the zygote which independently congress the maternal and paternal chromosomes and then must be aligned to execute the first division faithfully. This intriguing spindle assembly revealed the mechanism behind the long-standing observation that parental genomes occupy separate nuclear compartments in the two cell embryo and provides a likely rationale for erroneous divisions into more than two blastomeric nuclei observed in other mammalian zygotes, including human. Indeed, preventing the alignment of the two spindles after the assembly gives rise to multi-nucleated two-cell embryos in mouse. In mouse zygotes the alignment is rather reliable if not artificially perturbed, but in zygotes of other mammalian species it seems to be much less faithful. While the discovery of the dual spindle in mammalian zygotes has provided important new basic insights into the first mitotic division, the molecular mechanisms underlying dual spindle formation are still elusive. In this project, I established functional live-imaging analysis for the mouse zygote by combining advanced light sheet technics and molecular perturbations. With this approach, I was able to dissect the molecular mechanisms of dual spindle assembly and alignment in the first division. Indeed, I identify the major microtubules (MTs) nucleation sites and pathways responsible for dual spindle formation. Moreover, I determined the molecule essential for dual spindle alignment. Together with detailed molecular analysis of the molecules I identified, I established a new molecular model for the dual spindle formation in the mouse zygote.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

The first embryonic division after fertilization is essential for development of the organism and has to promote the union of the parental genomes. My host lab recently showed that in mammalian zygotes two bipolar spindles form, which first independently congress the maternal and paternal chromosomes and then must be aligned in parallel for a faithful division. The novel dual spindle assembly provided a likely rationale for erroneous divisions into more than two blastomeric nuclei observed in human fertility treatment. Indeed, preventing the alignment of the two spindles gives rise to multi-nucleated two-cell embryos also in mice. Due to its recent discovery and the difficulty of imaging in the light sensitive zygote, dual spindle assembly and function remains elusive. It is for example unclear what the contribution of cytoplasmic versus chromosomal microtubule (MT) nucleation is for forming two spindles and why spindle alignment is error-prone and variable between different mammals. Recent advances in microscopy in my host lab now enable me to address these questions. In my project, I will dissect the mechanism of dual spindle assembly and function by combining light sheet microscopy, computational image analysis, and molecular perturbation. To achieve this, I will perform 4D imaging of live mouse zygotes at high resolution that allows me to track individual nucleation sites as well as MT tips. This will allow me to generate the first spatial map of MT nucleation and assess what the contribution of the two MT populations for dual spindle assembly is. Moreover, I will test which MT nucleation pathway is essential for dual spindle assembly by molecular perturbations. Finally, I will check if errors in spindle alignment are the cause of parental genome loss, by identifying the key alignment factors and validate them in model organisms with different alignment fidelities. Thus, my studies will improve our understanding of cell division in mammals and human infertility.

Оригинален текст от CORDIS (на английски).

Участници

EUROPEAN MOLECULAR BIOLOGY LABORATORY · HeidelbergКоординаторГермания