Integrating systems biology and transgenic technologies to unlock the secrets of Sertoli cell development and function

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Adult male fertility and wellbeing are dependent upon appropriate fetal and postnatal testis development. This proposal is designed to develop our fundamental understanding of testis development through a combination of cell ablation studies and generation of a computer modelling system. Early events in testis development are induced by Sertoli cell (SC) differentiation which leads to formation of the seminiferous tubules and development of the fetal Leydig cells (LC) and peritubular myoid cells (PTMC). We do not know, however, the extent to which the SC remain central to testis biology thereafter, beyond local maintenance of spermatogenesis. To identify the role of the SC in overall testis biology we have generated a mouse line that expresses the simian diphtheria toxin receptor (DTR) specifically in the Sertoli cells. Mice normally lack a functional DTR so that treatment of these animals with diphtheria toxin (DTX) will lead to specific ablation of the SC. This will allow us to determine what happens to the testis if SC are ablated at different stages of development. In preliminary experiments with neonatal mice we have shown that a single injection of DTX causes near total SC ablation with no other harmful effects on the mice. We now propose to use this model system to determine the role of the SC in (i) PTMC, LC and gonocyte survival, function and development in the fetus (ii) adult LC differentiation, development and function and (iii) PTMC function and differentiated status in the adult animal. In addition, through partial ablation of the SC, our studies will show how adaptive the remaining SC are during proliferation and following final differentiation. Data from these studies will be integrated into a comprehensive in silico model of testis development and function. This will enhance our understanding of the ongoing biological processes and will provide the opportunity to test hypotheses related to testis development, function and dysfunction.

Beneficiaries
Immediate beneficiaries will be research professionals. It is anticipated that this will expand over time to include livestock breeders, veterinarians and healthcare professionals and the ageing population as this research impacts on our understanding of testis development and its role in determining adult health and fertility. Through public engagement there will also be benefit to the general public.

How will they benefit
The basic nature of the proposed work means that it is unlikely to have immediate impact beyond research professionals but, in the longer term, the impact of this work will extend to those who are engaged in animal breeding, infertility and male reproductive health. Cattle fertility in the UK has been in declinefor a numbers of years which has a major impact on the economics of the industry (1). The underlying reasons for this subfertility are diverse but seriously deficient semen quality is seen in a significant number of young bulls indicating that male reproductive dysfunction is an important contributory factor (2). Human infertility is also an increasing problem in the developed world with male factors the single biggest cause. There is also good evidence that human reproductive health is declining and that the origins of this decline are during fetal testicular development. Increased understanding of the basics of male reproduction will, therefore, have an impact on the pregnant woman or animal as well as the professionals who advise or maintain them. In addition, there is growing evidence that testicular androgens contribute significantly to the well-being of middle-aged and ageing males. Low testosterone, for example, is linked to metabolic syndrome which increases the likelihood of developing cardiovascular disease or diabetes during adult life and dementia during ageing. The studies outlined here will impact directly on our understanding of the development and maintenance of the Leydig cells - the testicular cell type that produces androgen. In the longer term this is likely to increase the chances of ameliorative treatment for these conditions and, thereby, have impact on healthcare professionals and patients.
This project will provide benefit to the general public through a greater understanding of reproduction and reproductive health and the issues facing both the individual and wider society. Greater awareness of the health issues will, for example, encourage pregnant women to avoid the kinds of lifestyles and behaviours that may affect reproductive development.
Economic Impact: We don't expect data or models to arise from this project that would be commercially sensitive. However, we have previous experience of commercial licencing of mouse models arising from our work (3), and we will liaise closely with Edinburgh Research and Innovation to protect and exploit any IP arising from our work.
Training: The new staff will join vibrant research laboratories, which are actively developing and exploiting new methodologies. They will benefit from the research environment and they will develop experience and knowledge of techniques in transgenics, molecular genetics, immunohistochemistry, transcript measurement, stereology and systems modelling, all of which are in both academic and commercial demand. TF acts as convenor of an undergraduate course in systems biology at the University of Edinburgh and students will receive training in computer modelling using and populating our in silico model. Staff will also be expected to attend relevant courses run by the lead Institutes which are designed to improve skills such as time management and staff supervision and they will be encouraged to join the public engagement outreach of the group, and will receive formal training on media and public engagement.
(1) Royal M, et al 2000 Vet J 160, 53-60. (2) Revell SG et al 2007 http://www.bsas.org.uk/downloads/animalbytes/Dairycow_Fertility.pdf (3) Smith et al 2011, CardioRes 90,182