Award details

FSTL3: A Crucial Regulator of Sertoli Cell Proliferation

Reference	BB/N009886/1
Principal Investigator / Supervisor	Dr Abir Mukherjee
Co-Investigators / Co-Supervisors
Institution	Royal Veterinary College
Department	Comparative Biomedical Sciences CBS
Funding type	Research
Value (£)	417,933
Status	Completed
Type	Research Grant
Start date	28/09/2016
End date	27/03/2020
Duration	42 months

Abstract

Follistatin-like 3 (FSTL3) is a secreted glycoprotein that binds and inhibits a subset of transforming growth factor beta (TGFbeta) ligands, including activin. To reveal its physiological roles we generated FSTL3 gene-deleted mice (FSTL3 KO). FSTL3 is strongly expressed, like activin, in the testis. We have recently shown that FSTL3 gene deletion increases testicular size, primarily via the increase in Sertoli cell numbers, and blocks age-related testicular size regression in these mice. Here we will test the hypothesis that testicular FSTL3 expression is essential for limiting Sertoli cell number and age-related decline in testicular function. We will first ascertain whether there is continued Sertoli cell proliferation in the absence of FSTL3. Also, whether this increased proliferation affects the differentiation status of Sertoli cells. Further, using Sertoli cell-specific, adult-induced or global FSTL3 knockout mice we will elucidate the roles of FSTL3 in Sertoli cell and germ cell proliferation, key determinants of the maintenance of testicular function. Specifically we will investigate whether 1) FSTL3 action in Sertoli cell alone is sufficient for limiting Sertoli cell numbers and testicular size or whether there is a requirement of a systemic FSTL3 effect; 2) Sertoli cell proliferation can be induced beyond the early post-natal period. We will also identify the signalling pathways and gene transcription events, influenced by FSTL3, that are crucial for maintaining testicular size in the FSTL3 KO and conversely those that are essential for age-dependent testicular regression. Our findings will define the processes underpinning the regulation and maintenance of testicular size during adulthood and ageing, and will support development of preventative and therapeutic strategies for testis-dependent reproductive disorders including male infertility.

Summary

Notwithstanding current world population infertility in humans is on the rise. 1 in 10 couples is infertile and in about a third of the cases, the defect arises from the male. Testicular defects are among the principal causes of reproductive deficit in males. Perhaps due to environmental effects male infertility in animals is also on the rise. This has most likely contributed to the reduction in numbers of many animal species in the wild. Understanding mechanisms that regulate testicular development and function is therefore essential for development of therapeutic strategies to alleviate male infertility disorders. The two major functions of the testis are to produce testosterone and sperm throughout the reproductive life of the species. Generally this begins at puberty when testicular size increases. Increased testicular size is an indicator of active generation of sperm and testicular function. There is, however, a need for age-related waning of testis function so that mutations accumulated with age are not propagated in the population. For seasonal breeders an additional requirement is the cyclical increase and decrease of the testis with the beginning and end of each breeding season. Sertoli cells (SC) in the testis allow for the duplications and development of the cells that give rise to sperm and generally the total number of germ cells produced depends on the number of SC in a testis. This number is fixed very early in life and normally does not change with age. What is not clear is how the number of SC is determined and whether SC numbers in a testis can be increased later on in life. It is also unclear how testis size reduction is controlled in an age or season dependent manner. We have found that a natural cell product, follistatin-like 3 (FSTL3) might be crucial in regulating testicular development. Our findings in genetically modified mice lacking FSTL3 in all cells show increased testis size, and a lack of testis size reduction with age. Also, within the testis there is an increase in SC numbers and related increase in cells that give rise to sperm. We, therefore, hypothesise that testicular FSTL3 action is essential for limiting testicular size and age-related decline in testicular function. There are only two other mouse models with increased testis size, but neither of these have a block in age-dependent reduction of testicular size. Our FSTL3 deletion mouse model, therefore, allows us to ask several crucial questions regarding testis development and function. Here we will first determine whether SC multiplication can be increased by reducing FSTL3 in mice and in tissue culture cells. We will then investigate whether SC numbers, can be increased by deleting FSTL3 only in the SC. This will demonstrate whether SC numbers are controlled by local FSTL3 expressed in the SC or whether there is a systemic requirement for FSTL3 production. Furthermore, we will address whether removing FSTL3 after puberty increases SC numbers. This will demonstrate whether SCs can multiply beyond the first few days after birth, therefore providing the possibility of a therapeutic strategy of inducing SC growth and fertility in infertile males with limitingly small testes. Finally, we will identify which genes and cellular signalling pathways FSTL3 may influence to limit testicular size and help achieve reduction of testis size with age. Our research will, therefore, identify how FSTL3 regulates testis development and function and helps limit reproduction with age. We will be identify the molecular mechanisms of these actions, whether FSTL3 dependent SC number regulation is achieved through its expression solely in SC and whether SC can be induced to grow, by removing FSTL3 at any time after birth. The contributions from this work to our understanding of the processes underlying testis development may support development of preventative and therapeutic approaches to dealing more effectively with male infertility.

Impact Summary

One of the most common disorders across all species is infertility, which in humans is frequently associated with testicular development and function. About 1 in 10 couples are infertile and infertility is on the rise. This is also true for companion and wild animal species. For humans extensive hormone therapy, in vitro fertilisation etc are common avenues of therapy but these are not always successful and often are detrimental to the emotional wellbeing of the people affected. Effective therapeutic interventions are desperately needed The proposed work is focused on elucidating the mechanisms by which FSTL3 regulate Sertoli cell proliferation, testicular development, function and age-related reduction of testicular size. A greater appreciation of how Sertoli cell proliferation and related spermatogenesis is controlled will offer routes towards treatment of male infertility arising out of reduced testicular size and function. Hence, the contributions of this work to our understanding of the processes underlying testis development, function and its regulation may support development of preventative and therapeutic approaches to dealing more effectively with male infertility related to testicular dysfunction. The following groups will benefit: 1. Industry: These results will clearly be valuable to the pharmaceutical and biotechnology industries with interests in novel therapeutics for male infertility. Findings related to maintenance of male fertility in mice might translate into alleviating human infertility 2. Policymakers and government agencies: Indirectly, The NHS, DEFRA and animal health and welfare charities will benefit from insights into testicular health revealed by our studies since loss of testicular function including that in chemotherapy patients is responsible for significant healthcare costs, as well as a factor that contributes to the lowering of quality of life. 3. Society: In the long term, the ultimate beneficiaries of the research will be human, and companion and performance animal patients along with their carers, dependants or owners. Loss of or reduced testicular function leads to severe mental anguish, stress and strongly affects emotional well-being in couples wishing to conceive. 4. Academics: Academics researching in a number of fields across biology, medicine and ageing will benefit, as outlined in the "academic beneficiaries" section of this proposal. The most immediate impact may be for reproductive biology researchers who will gain new insight into the control of postnatal testis development.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	X – not assigned to a current Research Topic
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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