Telephone: +44 (0)131 242-9111
Professor Lee Smith’s group focus upon all aspects of male reproductive health, specialising in identifying genetic and hormonal control signals that support male fertility and steroid hormone (testosterone) production
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Latest News from the Smith Group!
March 2014:A new paper from the group is accepted in Development
March 2014: Our recent paper on the role of Azi1 in cilia and sperm flagella formation receives a Faculty 0f 1000 ‘article recommendation‘
The adult testis is essentially a factory, which produces two key products, – the synthesis and secretion of steroid hormones, notably testosterone (made by testicular Leydig cells), and the production of mature sperm from spermatogonial stem cells (a process known as spermatogenesis). My group is working both to understand how these processes are regulated, and to develop new mechanisms to support both male fertility and life-long health and wellbeing.
Development of functional sperm from stem cells within the testis is a complex process. The genes that control this in men remain largely uncharacterised because it is very difficult to identify them. Our group use mouse models of male infertility to identify genes essential for sperm production. Through this process we are developing an understanding of the genetic networks and processes underlying testis function; knowledge that will be of benefit both to development of future treatments for male infertility and development of non-hormonal male contraceptives.
Steroidogenesis – testosterone production
In the male, androgens (such as testosterone) play significant roles both in male development and in adult reproductive function and general health. A reduction in androgen action during key stages of development results in incomplete physical masculinisation which can have life-long impacts (fetal programming), whilst disruption in androgen action in adulthood can lead to infertility, and has also been linked to several other widespread chronic conditions such as cardiovascular disease, obesity, depression and age-related deterioration in health.
It has been known for many years that testosterone signalling plays an essential role in regulating the process of spermatogenesis. However how this signal impacts upon each testicular cell-type has remained elusive. Testosterone acts by binding to the androgen receptor (AR) a single copy gene located on the X-chromosome which is expressed in several cell-types of the testis, but not germ cells (sperm). Thus testosterone’s effect upon sperm development must be indirect, acting via the supporting cell-types.
We have used the Cre/lox Recombination system to generate mouse models with selective ablation of AR from every somatic (supporting) cell-type of the testis. Our extensive analyses have characterized a previously undescribed paracrine-signalling network within the testis, which acts to support both sperm production and testosterone production.
Our current work is focused upon dissecting the mechanisms underlying this, using novel transgenic mouse models coupled to a wide variety of cutting edge molecular genetic and endocrinological techniques. In addition to this, we have extended our studies to investigate mouse models with targeted deletion of AR in the other body systems, including the cardiovascular system, adipose tissue and prostate.
Together, these investigations highlight a body-wide and lifelong role for androgen-signalling in supporting lifelong health and wellbeing in men. Our future focus is now on understanding how androgen production is controlled within the testis and how this influences not only male fertility, but also other important clinical problems such as cardiovascular disease, diabetes, and age-related conditions.
A Section through an adult testis showing seminiferous tubules (outlined by smooth muscle actin – blue) containing developing sperm (DNA – Green). Note that Androgen (testosterone) Receptor (Red) is expressed in several somatic cell types but is absent from developing sperm. Testosterone control of spermatogenesis therefore relies on a complex network of signals between these supporting cell types and the developing sperm.
Current research projects
- The Genetic and Hormonal Control of Male Reproductive Health and Fertility.
- Testis Development and Function in Relation to Disorders of Reproductive and General Health in Males (with Professor Richard Sharpe).