Professor of Reproductive Physiology
Tel: +44 (0)1223 333881 (office) 765302 (lab), Fax: +44 (0)1223 333840, E-mail: firstname.lastname@example.org
My group uses transgenic mouse models of human disease to understand the mechanisms of disease progression and to develop new treatment strategies. We are particularly interested in the role that diseases genes play in normal development and in understanding the complex developmental program of gametogenesis. This technology centres around the use of genetically manipulated embryonic stem cells to generate mice carrying specific mutations.
Reproductive physiology research themes (previous research areas)
Regulation of gametogenesis
My group has played a significant role in reproductive physiology by increasing our understanding of several aspects of gametogenesis and fertility. We were one of the first groups in the world to elucidate the function of the c-mos proto-oncogene in oogenesis. Female mice with a non-functional c-mos gene have reduced fertility because of the failure of mature eggs to arrest during meiosis. These results demonstrated that a major role for the MOS protein is to prevent the spontaneous parthenogenetic activation of unfertilized eggs.
We have used gene targetted mice to define the role of specific genes in spermatogenesis. Disruption of the cell-cycle gene, cyclin A1 has been show by others to be required for spermatogenic meiosis and we have confirmed and extended this data. We have also found however, that the amount of cyclin A1 protein influences the fertility of male mice and its action is modulated by genetic background. On an outbred genetic background (129S6/SvEv x MF1), Ccna1tm1Col +/– mice show reduced sperm production and fertility. This is even more pronounced on an inbred genetic background (129S6/SvEv) where Ccna1tm1Col +/– male mice are sterile due to a severe reduction in the total number of sperm.
Colledge, W.H., Carlton, M.B.L., Udy, G.B. and Evans, M.J. (1994). Disruption of c-mos causes parthenogenetic development of unfertilized mouse eggs. Nature 370:65-68. (PDF)
Russ, A.P., Wattler, S., Colledge, W.H., Aparicio, S.A.J.R., Carlton, M.B.L., Pearce, J.J., Barton, S.C., Surani, M.A., Ryan, K., Nehls, M.C., Wilson, V., Evans, M.J. (2000) Eomesodermin is required for mouse trophoblast development and mesoderm formation. Nature 404:95-99. (PDF)
Van der Meer, T., Chan, W.Y., Palazon, L.S., Nieduszynski C, Murphy M, Sobczak-Thepot J, Carrington M, Colledge WH. (2004) Cyclin A1 protein shows haplo-insufficiency for normal fertility in male mice. Reproduction 127: 503-511. (PDF)
Neuroendrocrine control of fertility
My current research is focused on characterization of key molecules that are required for the maintaining mammalian fertility. We have identified a G-protein coupled receptor (GPR54) that is a vital regulator of the mammalian reproductive axis. Mutant mice lacking GPR54 have immature reproductive organs and low levels of sex steroids and gonadotrophic hormones, but normal levels of GnRH in the hypothalamus.
Identifying the role of Kiss1/Gpr54 in regulating mammalian fertility has created a new field of research in reproductive physiology and provided an insight into the mechanisms by which sex steroids may regulate hypothalamic reproductive functions.
Fundamental knowledge gained from this work will be relevant in some cases of precocious puberty or idiopathic infertility and possibly in the regulation of spontaneous abortions and cancer management. By understanding the molecular, cellular and hormonal control mechanisms in an integrated system, it might be possible to develop novel compounds to regulate the reproductive axis and develop new contraceptives or substances that induce earlier puberty or re-entry into the breeding cycle in domestic animals.
Seminara, S.B., Messager, S., Chatzidaki, E.E., Thresher, R.R., Acierno, J.S., Shagoury, J.K., Bo-Abbas, Y., Kuohung, W., Schwinof, K.M., Hendrick, A.G., Zahn, D., Dixon, J., Kaiser, U.B., Slaugenhaupt, S.A., Gusella, J.F., O'Rahilly, S., Carlton, M.B., Crowley, W.F., Aparicio, S.A. and Colledge, W.H. (2003). The GPR54 gene as a regulator of puberty. N Engl J Med 349:1614-1627. (PDF)
Messager, S., Chatzidaki, E.E., Ma D., Hendrick, A.G., Zahn, D., Dixon, J., Thresher, R.R., Malinge, I., Lomet, D., Carlton, M.B., Colledge, W.H., Caraty, A. and Aparicio, S.A. (2005). Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci USA 102:1761-1766. (PDF)
d'Anglemont de Tassigny, X., Fagg, L.A., Dixon, J.P., Day, K., Leitch, H.G., Hendrick, A.G., Zahn, D., Franceschini, I., Caraty, A., Carlton, M.B., Aparicio, S.A. and Colledge, W.H. (2007). Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc Natl Acad Sci USA 104:10714-10719. (PDF)
d'Anglemont de Tassigny, X.A., Fagg, L.A., Carlton, M.B. and Colledge, W.H. (2008). Kisspeptin can stimulate GnRH release by a direct action at GnRH nerve terminals. Endocrinology 149:3926-3932.
d'Anglemont de Tassigny, X., Ackroyd, K.J., Chatzidaki, E.E. and Colledge, W.H. (2010). Kisspeptin signaling is required for peripheral but not central stimulation of gonadotropin-releasing hormone neurons by NMDA. J Neurosci 30:8581-8590.
d'Anglemont de Tassigny, X. and Colledge, W.H. (2010). The role of kisspeptin signaling in reproduction. Physiology 25:207-217.
Hanchate, N.K., Parkash, J., Bellefontaine, N., Mazur, D., Colledge, W.H., d'Anglemont de Tassigny, X., Prevot, V. (2012). Kisspeptin-GPR54 signaling in mouse NO-synthesizing neurons participates in the hypothalamic control of ovulation. J Neurosci 32:932-945.
Prof S Aparicio, Department of Pathology and Laboratory Medicine, University of British Columbia
Dr Alain Caraty/Dr Isabelle Franceschini, Unité de Physiologie de la Reproduction et des Comportements, Université François Rabelais, Tours
Dr Anthony Davenport, Clinical Pharmacology Unit, BHF Human Receptor Research Group, University of Cambridge
Prof Allan Herbison, Centre for Neuroendocrinology and Department of Physiology, School of Medical Science, University of Otago
Above: Parthenogenic activation of mos–/– eggs. 4-week-old virgin female animals were superovulated with human chorianic gonadotropin (hCG). Photomicrographs are of eggs at times indicated (in h) after hCG administration (h0). Polar bodies indicated by arrowheads, pronuclei by arrows. Eggs isolated from normal animals had a single polar body while those from mutant mice had two polar bodies and no pronuclei. Approximately 40% of mutant eggs with two polar bodies maintained in culture developed a pronucleus, indicative of true parthnogenetic development.
Above: GPR54 in puberty. Illustration of wild type (left) and GPR54 mutant (right) mouse reproductive organs. Both male and female mutants are sterile and have immature reproductive organs and low levels of sex steroids and gonadotrophic hormones.