Professor William Colledge

Reproductive 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 genetically manipulated embryonic stem cells to generate mice carrying specific mutations.

You can also view my group's 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.

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.

Collaborators

Prof Allan Herbison, Physiology, Development and Neuroscience, University of Cambridge, UK

Dr Susan Jones, Physiology, Development and Neuroscience, University of Cambridge, UK

Prof Kevin O'Byrne, Kings College, University of London

Prof Manuel Tena-Sempare, University of Cordoba, Spain