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Do germline stem cells contribute to the reserve of oocytes in the mouse?

Reference	BB/D002583/1
Principal Investigator / Supervisor	Professor Maj Anita Hulten
Co-Investigators / Co-Supervisors	Dr Robert Old
Institution	University of Warwick
Department	Biological Sciences
Funding type	Research
Value (£)	186,382
Status	Completed
Type	Research Grant
Start date	01/03/2006
End date	28/02/2009
Duration	36 months

Abstract

It has been a long-held belief that, in most mammalian species, females have no capacity for adding to their germ cell supply in adult life. This view has recently been challenged, with evidence suggesting the existence of germline stem cells (GSCs) that can contribute to the reserve of oocytes in adult mice. In this project we aim to follow up and extend this work by investigating ovaries from postnatal, juvenile and adult female mice in order to (1) Identify putative GSCs by immunofluorescence image analysis of components of the meiosis-specific proteinaceous chromosome pairing complex, the Synaptonemal Complex (SC), (2) Document the synaptic efficacy as well as the crossover frequency distribution along the length of individual SCs in any such cells, (3) Find out if proliferating germ cells exist, using a combination of germ cell-specific antibodies and BrdU labelling, following promotion of meiosis by addition of certain growth factors to the medium in ovarian in vitro cell cultures, and (4) Trace the lineage of premeiotic germ cells into meiotic prophase by pulse BrdU experimentation of in vitro cultured ovarian fragments. It is essential to recognise that whether or not we can but refute the hypothesis of the existence of GSCs in the postnatal ovary, this project will provide important new information with respect to for example (1) SC proteins and prophase I staging in mouse foetal oocytes, where much less information is currently available than in males at the same stages, (2) Characteristics including crossover frequency and distribution of prophase I stages already known to exist at birth and for the first few days thereafter, (3) The true identity of common postnatal germ cells, previously suggested to be arrested oogonia, and (4) The potential of different growth factors to enhance germ cell proliferation, and meiotic maturation, long term.

Summary

In this project we aim to work on and expand a suggestion made by a research group in the USA that renewal of egg-producing cells can take place in the adult ovary. This research work was performed in mice but was thought to imply that the same will happen in human females. This report, published in the prestigious scientific journal Nature, created much interest both among scientists and the public media. This is so, because it has been believed for a long time that from birth of mammalian females (including girls) and onwards there is a continuous decline in the number of egg-producing cells until total depletion, leading to menopause. If a topping up process exists during adulthood, it would prompt a major rethink of many of our views in reproductive biology, touching upon everything from fertility and aging to the childbearing capabilities of young cancer patients undergoing therapy. Importantly the topping up process could be exploited in situations of disease or chemotherapy, so that by stimulating the process, fertility could be maintained. We are seeking resources to be able to follow up and expand this work in mice, using a combination of more advanced microscopy and cell growth technology. Even if we cannot confirm the observations of the USA group in itself, the project should lead to additional important information to be obtained with respect to egg-producing cells in mice females, information that could then be extrapolated to the situation in women.

Committee	Closed Committee - Genes & Developmental Biology (GDB)
Research Topics	Stem Cells
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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