Professor of Reproductive Physiology
- Developmental biology and reproduction:
Transgenic mouse models of human disease: reproductive physiology, cystic fibrosis, and cardiac physiology
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
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.
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.
Prof S Aparicio, Department of Path. and Lab. Med., University of British Columbia
Dr Alain Caraty/Dr. Isabelle Franceschini, Unité de Physiologie de la Reproduction et des Comportements, Univ. Tours
Dr Anthony Davenport, Clinical Pharmacology Unit, BHF Human Receptor Research Group, University of Cambridge
Dr A. Grace, Department of Biochemistry, University of Cambridge
Prof Allan Herbison, Centre for Neuroendocrinology and Department of Physiology, School of Medical Science, University of Otago
Prof Chris Huang, Department of PDN, Cambridge
Doran, J., Walters, C., Kyle, V., Wooding, P., Hammett-Burke, R. and Colledge, W.H. (2016). Mfsd14a (Hiat1) gene disruption causes globozoospermia and infertility in male mice. Reproduction 152:91-99.
Herreboudt, A. M., Kyle, V. R., Lawrence, J., Doran, J. and Colledge, W. H. (2015). Kiss1 mutant placentas show normal structure and function in the mouse. Placenta 36:52-58.
Bellefontaine, N., Chachlaki, K., Parkash, J., Vanaker, C., Colledge, W.H., d’Anglemont de Tassigny, X., Garthwaite, J., Bouret, S.G., and Prevot, V. (2014). Leptin facilitates reproduction through neuronal nitric oxide signaling in the hypothalamic preoptic region. J Clin Invest 124(6):2550–2559.
Hanchate NK, Parkash J, Bellefontaine N, Mazur D, Colledge WH, 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
d'Anglemont de Tassigny X, Colledge WH, (2010), The role of kisspeptin signaling in reproduction, Physiology, 25:207-217
d'Anglemont de Tassigny X, Ackroyd KJ, Chatzidaki EE, Colledge WH, (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, Fagg LA, Carlton MB, Colledge WH, (2008), Kisspeptin can stimulate GnRH release by a direct action at GnRH nerve terminals, Endocrinology, 149:3926-3932
d'Anglemont de Tassigny X, Fagg LA, Dixon JP, Day K, Leitch HG, Hendrick AG, Zahn D, Franceschini I, Caraty A, Carlton MB, Aparicio SA, Colledge WH, (2007), Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene, Proc Natl Acad Sci USA, 104:10714-10719
Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, Colledge WH, Caraty A, Aparicio SA, (2005), Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54, Proc Natl Acad Sci USA, 102:1761-1766
Van der Meer T, Chan WY, Palazon LS, 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
Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O'Rahilly S, Carlton MB, Crowley WF, Aparicio SA, Colledge WH, (2003), The GPR54 gene as a regulator of puberty, N Engl J Med, 349:1614-1627
Russ AP, Wattler S, Colledge WH, Aparicio SAJR, Carlton MBL, Pearce JJ, Barton SC, Surani MA, Ryan K, Nehls MC, Wilson V, Evans MJ, (2000), Eomesodermin is required for mouse trophoblast development and mesoderm formation, Nature, 404:95-99
Colledge WH, Carlton MBL, Udy GB, Evans MJ, (1994), Disruption of c-mos causes parthenogenetic development of unfertilized mouse eggs, Nature, 370:65-68