Understanding the Balbiani body: A super-organelle linked to dormancy in oocytes

Project Information

DORMANTOOCYTE

Grant agreement ID: 759107

DOI

10.3030/759107

Project closed

EC signature date 19 September 2017

Start date 1 March 2018

End date 31 December 2023

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 381 286,00

EU contribution

€ 1 381 286,00

Coordinated by

FUNDACIO CENTRE DE REGULACIO GENOMICA
Spain

Periodic Reporting for period 4 - DORMANTOOCYTE (Understanding the Balbiani body: A super-organelle linked to dormancy in oocytes)

Reporting period: 2022-09-01 to 2023-12-31

Summary of the context and overall objectives of the project

Female germ cells, oocytes, are highly specialised cells. They ensure the continuity of species by providing the female genome and mitochondria along with most of the nutrients and housekeeping machinery the early embryo needs after fertilisation. Oocytes are remarkable in their ability to survive for long periods of
time and retain the ability to give rise to a young organism while other cells age and die. Surprisingly little is known about oocyte dormancy. A key feature of dormant oocytes of virtually all vertebrates is the presence of a Balbiani body, which is a non-membrane bound compartment that contains most of the organelles in dormant oocytes and disappears as the oocyte matures.
The goal of this research proposal was to combine genetic and biochemical perturbations with imaging and the state of the art proteomics techniques to reveal the mechanisms dormant oocytes employ to remain viable. Our previous research showed that the Balbiani body forms an amyloid-like cage around organelles that could be protective. Following this discovery, we identified a large number of unanswered questions about the cell biology of a dormant oocyte. In DORMANTOOCYTE, we addressed -
1) What is the metabolic nature of organelles in dormant oocytes?
2) How does the Balbiani body disassemble and release the complement of organelles when oocytes start to mature?
3) What is the structure and function of the Balbiani body in mammals?

We found that oocyte mitochondria are special such that they do not have a major protein complex, previously thought to be required for mitochondrial activity (Rodriguez et al., 2022, Nature). Moreover, a fruitful collaboration with Dr. Alex Holehouse’s lab revealed distinct features of the protein which holds the Xenopus Balbiani bodies in an amyloid network, opening up the door to further manipulations of physiological amyloids (Holehouse et al., 2021). Finally, we have developed and optimised methods to study mammalian primordial oocytes, and performed a comparative cellular characterisation of dormant oocytes in vertebrates. This study revealed the relative advantages and limitations of choosing different model organisms for studying oocyte dormancy (Dhandapani et al., 2022).

Overall, this project provided groundbreaking insights into the mechanisms that are employed by dormant oocytes to be viable in their long lifespan. The discoveries not only advance the scientific understanding of cellular processes but also hold promise for practical applications in reproductive medicine. The optimized methods for studying primordial oocytes also offer a valuable resource to the community. Overall, the project's conclusions underscore its significance in contributing to both scientific knowledge and potential societal impacts in the field of reproductive biology.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

1) We discovered that early oocytes suppress ROS levels by downregulating mitochondrial complex I. This evolutionary conserved strategy allows longevity while maintaining biological activity. Our findings also clarify why complex I related hereditary mitochondrial diseases do not lead to subfertility and have significant translational potential as they suggest strategies to prevent chemotherapy-induced infertility in young women (Rodriguez et al., 2022, Nature).
2) We have developed and optimised methods to study primordial oocytes live, and performed a comparative cellular characterisation of dormant oocytes in vertebrates. This study revealed the relative advantages and limitations of choosing different model organisms for studying oocyte dormancy (Dhandapani et al., 2022).
3) A very fruitful collaboration with Dr. Alex Holehouse’s lab (Wustl) revealed distinct features of the protein which holds the Xenopus Balbiani bodies in an amyloid network, opening up the door to further manipulations of physiological amyloids (Holehouse et al., 2021).

These results are disseminated in the following seminars and congresses, as well as in other public outreach platforms:
Keynote Lectures:
• SEBBM, Spanish Biochemical Society, Loreal & Unesco Women in Science Plenary Lecture. Santander, Spain (2018)
• 8th Iberian Prion Congress. Castelo Branco, Portugal (2019)
• 12th IGE3 Annual Meeting Geneva-Switzerland (2023)

Invited Symposia Talks (only in-person talks are listed, since 2021):
• EMBO Symposium “Cellular Mechanisms Driven by Phase Separation”. Heidelberg, Germany (2022)
• 123rd International Titisee Conference “RNA as a driving force in cellular organisation and function”. Black Forest, Titisee, Germany (2022)
• 8th International Congress of the Molecular Biology Association of Turkey, Istanbul, 2022.
• Vienna BioCenter (VBC) PhD Symposium “Pushing boundaries”. Vienna, Austria, 2022.
• International Symposium on Totipotency&Germ Cell Development, Fukuoka, Japan 2022
• Catalonia Cell and Tissue Research (CATCAT) Meeting, Barcelona, Spain, 2022
• Sabri Ülker Center Symposium, Metabolism and Life, Istanbul, Turkey, 2023
• CNRS Jacques Monod Conference "Growth and regeneration during development and aging” Roscoff, France, 2023.
• European Society of Human Reproduction and Embryology (ESHRE) 39th Annual Meeting Copenhagen, Denmark, 2023.
• MRC Laboratory of Molecular Biology PhD Symposium. Cambridge, UK, 2023
• Gordon Research Conference “Molecular Membrane Biology.” Andover, NH, USA, 2023
• EMBO Workshop “Developmental metabolism: flows of energy, matter, and information” Heidelberg, Germany, 2023
• European Developmental Biology Congress, Barcelona hub, Spain, 2023
• 25th EMBL PhD Symposium, Heidelberg, Germany, 2023.

Invited Seminars (only in-person talks are listed, since 2021):
• CIRB, Center for Interdisciplinary Research in Biology, Paris, France (2022)
• Andalusian Center of Developmental Biology (CABD) Sevilla, Spain (March 2023)
• Francis Crick Institute London, United Kingdom (April 2023)
• Department of Molecular Biology and Genetics Faculty of Arts and Sciences Bogazici University Istanbul, Turkey (May 2023)
• Koch Institute For Integrative Cancer Research at MIT, Boston, USA (July 2023)
• Babraham Institute Cambridge, UK (Oct 2023)
• Wellcome Sanger Institute, Cambridge, UK (Oct 2023)

Public Outreach:
Featured in newspapers such as: https://www.lavanguardia.com/ciencia/20230128/8708163/como-ovulos-conservan-fertilidad.html
STATNEWS: https://www.statnews.com/2022/07/20/why-eggs-can-survive-decades-without-signs-of-aging/
Participated in public outreach programs such as the science day in Barcelona.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

One of the distinguishing features of this proposal is that it aims to make progress in a very understudied subject in biology. Thus, it requires an innovative combination of recent technological advances and established techniques at any step; we optimised and successfully used SeaHorse, metabolomics and proteomics for the first time to our knowledge in dormant oocytes.