The interaction of steroid hormone receptors with FOXL2 during ovary development

About the project

About the Project A 2027 Crick PhD project with Robin Lovell-Badge. Project background and description Functional organ development requires the correct differentiation and spatial organisation of progenitor cells, where these can be anything from self-renewing stem cells through to committed intermediate cell types. We now know many of the signals and transcription factors used to direct the formation of ovaries or testes from common progenitor cell types in the embryo, or via in vitro differentiation from pluripotent stem cells (PSCs) [1]. However, the details count, and we still have much to discover about the role of specific genes and factors, including those that influence the maintenance of gonadal cell types within the gonads and how these function in the context of the animal. This includes their interaction with the pituitary and central nervous system, which is critical to their function, notably to the production of oocytes and sperm. FOXL2 is a transcription factor known to be involved in ovary development in several vertebrate species. In goats it plays an early role, as animals lacking it show a primary sex reversal, developing as XX males resembling normal XY siblings; the situation in the chick is similar, with testis-like organs developing instead of ovaries in ZW birds, although these are not quite like testes in ZZ control males. In the mouse, however, it has a largely redundant role during embryo development, but becomes essential postnatally to maintain granulosa cells (the somatic cells typical of the ovary that support the oocytes) [2]. We found that FOXL2 interacts with many other proteins, with the details changing between embryonic, newborn and adult ovaries [3]. Some of these interactors also play critical roles, with TRIM28 mutants having a similar but milder gonadal sex reversal phenotype, and USP7 mutants having a strong phenotype, with early impairment of follicle development leading to infertility. Other interactors include both estrogen and androgen receptors, but how these support or antagonise FOXL2 is not understood. Androgens are made by Leydig cells in the mouse testis from about embryonic day 13, as this first differentiates, whereas significant levels of estrogens are only made by the ovary around birth. Their production is then modulated by pituitary hormones. Androgens are also found in females; indeed high levels are associated with polycystic ovary syndrome (PCOS) in women. However, it is technically challenging to measure the activity of the receptors and levels of the ligands in vivo. This project will use genetic and molecular approaches to explore the interaction of these receptors with FOXL2 in more detail and to develop in vitro (mouse and possibly human) and in vivo methods to assay their activity in living cells. Reporters for steroid hormone receptor activity have been developed for some animals, including mice [4], but there is scope for improvement, especially to allow live cell imaging. The project will investigate the effects of modulating ligand levels and receptor function on the gene regulatory networks we and others have characterised during ovary development and explore the effects on the ‘ovarian reserve’ (oocyte complement), follicle growth and maturation, and fertility [5]. Candidate background Candidates should have a degree in relevant biological subject and some research experience, which could be as part of an MSc or MRES, or from working in a lab. I am particularly interested in receiving applications from those with knowledge developmental/stem cell biology, genetics, and molecular biology, with some practical experience of the latter. Experience of cell culture, imaging, and bioinformatics would all be useful, but are not essential. Training is available in these and other relevant techniques. Lab-specific question The project is concerned with the development, maintenance and function of the gonads, notably of the ovary. Please describe why you are interested in this aspect of reproductive biology, including why any research experience you have may be relevant?

Research areas