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
Support our Research
It is possible to support our research efforts through our Work With Us site.
Latest News from the Smith Group!
November 2013: A bumper end to the year with several new papers and books published (see publications below). More to come before 2014!
September 2013: Our recent collaboration with the group of Dr Pleasantine Mill who is based at the Institute for Genetics and Molecular Medicine, in Edinburgh has been accepted for publication in PLoS Genetics (see citation below).
The adult testis is essentially a factory which produces two key products under control from the brain; 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). These two processes are functionally linked, and my group has been working to characterise these interactions.
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 impact (fetal programming), whilst a reduction in androgen production in adulthood results in 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 t he 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 animal models which have selective ablation of AR from somatic (supporting) cells of the testis; Sertoli cells, Peritubular Myoid cells, and Vascular Smooth Muscle cells, respectively. Loss of AR in Sertoli cells results in male infertility because maturation of germ cells into sperm is blocked during meiosis. Whereas loss of AR in Peritubular Myoid cells results in male infertility through loss of a proportion of germ cells at all stages of maturation.
Further to this, we have also demonstrated that ablation of androgen signalling in each of these cell-types impacts upon steroidogenesis in another cell-type, the testicular Leydig cells, suggesting a large-scale, androgen-dependent paracrine signalling network exists within the testis. 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 somatic cells of the testis (Leydig, Vascular Smooth Muscle) and i n other regions of the male urogenital system such as the Wolffian duct and its derivatives (seminal vesicles, epididymides).
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).
Selected Recent Publications
O’Hara L, York JP, Zhang P, and Smith LB (2013) Targeting of GFP-Cre to the mouse Cyp11a1 locus both drives Cre Recombinase expression in steroidogenic cells and permits generation of Cyp11a1 knock out mice. PLoS One (In Press)
Mitchell RT, Camacho-Moll M, Macdonald J, Anderson RA, Kelnar CJH, O’Donnell, M, Sharpe RM, Smith LB, Grigor KM, Wallace WHB, Stoop H, Wolffenbuttel KP, Donat R, *Saunders PTK and *Looijenga LHJ. (2013) Intratubular germ cell neoplasia of the human testis: heterogeneous protein expression and relation to invasive potential Modern Pathology (In Press)
Hall EA, Keighren M, Ford MJ, Davey T, Jarman AP, Smith LB, Jackson IJ and Mill P. (2013) Acute versus chronic loss of mammalian Azi1/Cep131 results in distinct ciliary phenotypes. PLoS Genetics (In Press)
Smith LB and Walker WH. (2013) Hormone Signaling in the Testis. In Knobil and Neill’s Physiology of Reproduction (Fourth Edition) (In Press)
Smith LB, Mitchell RT and McEwan IJ. (2013) Testosterone: From Basic Research to Clinical Applications. Springer Briefs – Reproductive Biology Series
Mitchell R, Sharpe RM, Anderson RA, McKinnell C, Macpherson S, Smith LB, Wallace WHB, Kelner C, and van den Driesche S (2013) Diethylstilboestrol exposure does not reduce testosterone production in human fetal testis xenografts. PLoS ONE 8(4): e61726. doi:10.1371/journal.pone.0061726
Smith LB, Milne L, Nelson N, Eddie S, Brown P, Atanassova N, O’Bryan MK, O’Donnell L, Rhodes D, Wells S, Napper D, Nolan P, Lalanne Z, Cheeseman M and Peters J. (2012) KATNAL1 Regulation of Sertoli Cell Microtubule Dynamics is Essential for Spermiogenesis and Male Fertility. PLoS Genetics PLoS Genet 8(5): e1002697. doi:10.1371/journal.pgen.1002697
O’Donnell L, Rhodes D, O’Connor AE, Smith SJ, Clark B, Borg C, Whittle B, Merriner DJ, Smith LB, McNally F, de Kretser DM, Goodnow CC, Ormandy CJ, Jamsai D and O’Bryan MK. (2012) An essential role for p80 katanin and microtubule severing in male gamete production. PLoS Genetics PLoS Genet 8(5): e1002698. doi:10.1371/journal.pgen.1002698
Van den Driesche S, Walker M, McKinnell C, Scott HM, Eddie SL, Mitchell RT, Seckl JR, Drake AJ, Smith LB, Anderson RA and Sharpe RM (2012) Proposed Role for COUP-TFII in Regulating Fetal Leydig Cell Steroidogenesis, Perturbation of which leads to Masculinization Disorders in Rodents. PLoS ONE 7(5): e37064. doi:10.1371/journal.pone.0037064
McInnes KJ, Smith LB, Hunger NI, Saunders PTK, Andrew R and Walker BR. (2012) Deletion of the Androgen Receptor in adipose tissue in male mice elevates retinol binding protein 4 and reveals independent effects on visceral fat mass and on glucose homeostasis. Diabetes 2012 Mar 13. [Epub ahead of print]
O’Hara L and Smith LB. (2012) Androgen Receptor Signalling in Vascular Endothelial Cells is Dispensable for Spermatogenesis and Male Fertility. BMC Research Notes 5:16
Dean A, Smith LB, Macpherson S and Sharpe RM. (2012) The effect of dihydrotestosterone exposure during or prior to the masculinization programming window on reproductive development in male and female rats. International journal of Andrology doi: 10.1111/j.1365-2605.2011.01236.x.
Welsh M, Moffat L, Belling K, Renato de França L, Segatelli T, Saunders PTK, Sharpe RM, and Smith LB (2012) Androgen Receptor Signalling in Peritubular Myoid Cells is Essential for Normal Differentiation and Function of Adult Leydig Cells. International Journal of Andrology 35: 25-40
Denison FC, Smith LB, Muckett PJ, O’Hara L,Carling D, Woods A. (2011) LKB1 is an Essential Regulator of Spermatozoa Release During Spermiation in the Mammalian Testis. PLoS ONE 6(12): e28306. doi:10.1371/journal.pone.0028306
Welsh M, Moffat L, McNeilly A, Brownstein D, Saunders PTK, Sharpe RM, Smith LB. (2011) Smooth muscle cell-specific knockout of androgen receptor: a new model for prostatic disease. Endocrinology. 152(9):3541-51.
Smith LB and Saunders PTK (2011) The Skeleton: the new controller of male fertility? Cell. 144(5) 642-643
O’Hara L, Welsh M, Saunders PTK and Smith LB (2011) Androgen Receptor Expression In The Caput Epididymal Epithelium Is Essential For Development Of The Initial Segment And Epididymal Spermatozoa Transit. Endocrinology 152 (2): 718-729 (Faculty of 1000 citation)
- O’Hara L, Welsh M, Saunders PTK and Smith LB (2011) Androgen Receptor Expression In The Caput Epididymal Epithelium Is Essential For Development Of The Initial Segment And Epididymal Spermatozoa Transit. Journal of Clinical Endocrinology and Metabolism – Translational Highlights 96(2) 555
- O’Hara L, Welsh M, Saunders PTK and Smith LB (2011) Androgen Receptor Expression In The Caput Epididymal Epithelium Is Essential For Development Of The Initial Segment And Epididymal Spermatozoa Transit. Endocrine Reviews – Translational Highlights 32(1) 152
Smith LB (2011) Good Planning and Serendipity: Exploiting the Cre/Lox system in the Testis. Reproduction. 141(2):151-61
Orr B, Vanpoucke G, Grace OC, Smith LB, Anderson RA, Riddick ACP, Franco OE, Hayward SW and Thomson AA. (2011) Expression of Pleiotrophin in the Prostate is Androgen Regulated and it Functions as an Autocrine Regulator of Mesenchyme and Cancer Associated Fibroblasts and as a Paracrine Regulator of Epithelia. Prostate. 71(3):305-17
Smith LB, Hadoke PWF, Dyer E, Denvir M, Brownstein D, Miller E, Nelson N, Wells S, Cheeseman M, and Greenfield A. (2010) Haploinsufficiency of the murine Col3α1 locus causes aortic dissection: a novel model of the vascular type of Ehlers Danlos Syndrome. Cardiovascular Research. doi: 10.1093/cvr/cvq356
Welsh M, Sharpe RM, Moffat L, Atanassova N, Saunders PTK, Kilter S, Bergh A, Smith LB, (2010) Androgen action via testicular arteriole smooth muscle cells is important for Leydig cell function, vasomotion and testicular fluid dynamics. PLoS One 5(10): e13632.
Welsh M, Moffat L, Jack L, McNeilly A, Brownstein D, Saunders PT, Sharpe RM, Smith LB. (2010) Deletion of androgen receptor in the smooth muscle of the seminal vesicles impairs secretory function and alters its responsiveness to exogenous testosterone and estradiol. Endocrinology. 151:3374-85.
Willems A, De Gendt K, Allemeersch J, Smith LB, Welsh M, Swinnen JV and Verhoeven G (2010) Early effects of Sertoli cell-selective androgen receptor ablation on testicular gene expression. Int J. Androl 33(3):507-1
Welsh M, Saunders PT, Atanassova N, Sharpe RM, Smith LB. (2009) Androgen action via testicular peritubular myoid cells is essential for male fertility. FASEB J. Dec; 23(12):4218-30 (Faculty of 1000 citation)
Smith LB, Saunders PTK (2009) What makes a man? The effect of androgen receptors on male fertility. The Biochemist 31:12-15
Welsh M, MacLeod DJ, Walker M, Smith LB and Sharpe RM. (2009) Critical androgen-sensitive periods of rat penis and clitoris development. International Journal of Andrology 32, 1–8
Welsh M, Sharpe RM, Walker M, Smith LB, Saunders PT. (2009). New insights into the role of androgens in Wolffian duct stabilization in male and female rodents. Endocrinology. 150: 2472-2480
Pastorelli LM, Wells S, Fray M, Smith A, Hough T, Harfe BD, McManus MT, Smith LB, Woolf AS, Cheeseman M, Greenfield A. (2009) Genetic analyses reveal a requirement for Dicer1 in the mouse urogenital tract. Mamm Genome. Volume: 20 Issue: 3 Pages: 140-151
Welsh M, Saunders PT, Fisken M, Scott HM, Hutchison GR, Smith LB, and Sharpe RM (2008) Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest 118: 1479-90
Smith LB, Willan J, Warr N, Brook FA, Cheeseman M, Sharpe R, Siggers P, Greenfield A. (2008). The Maestro (Mro) gene is dispensable for normal sexual development and fertility in mice. PLoS ONE. 3(12):e4091