Lovell-Badge lab Stem Cell Biology and Developmental Genetics Laboratory
: Areas of interest
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Figure 1: Sox9, a direct target of SRY, is required to initiate the differentiation of Sertoli cells typical of the testis. SOX9 maintains its own expression, directly and indirectly. SOX9 also represses genes that promote ovary development. In the absence of Sry, the Wnt signalling pathway and other ovary promoting factors, not all of which are known, serve to repress Sox9 and promote granulosa cell differentiation. The system remains remarkably labile. For example, the transcription factor FOXL2 is required in granulosa cells to repress Sox9 and to prevent them from turning into Sertoli cells even in the adult.
Embryo development relies on cells making choices about which cell type to become and whether to divide, move or die. Similar decisions are made by stem cells in adult tissues; these can be quiescent or activated, and they can self-renew and/or give rise to one or more differentiated cell types. These decisions rely on a combination of extrinsic factors provided by the cell's environment or niche, and intrinsic factors, notably transcription factors, that give cells their properties, including how they will respond to the external cues. The study of such decisions of cell fate forms the major focus of our work.
Sex determination is a paradigm for studying cell fate, and is a major topic of our research. During this process, cells of the early embryonic gonad have an additional choice to make: to become cells typical of testes or ovaries. In mammals this usually depends on the presence or absence of the Y chromosome (males are XY, females XX). This is due to just one gene on the Y, termed Sry, which encodes a transcription factor, SRY, characterised by an HMG box type of DNA binding domain. Such domains are present in proteins encoded by members of the Sox gene family, of which there are 20 in mammals.
Most of these genes are located on autosomes, except for Sry on the Y and Sox3, which is X-linked. The function and mechanisms of action of several of these SOX proteins has also been a major theme of our research, although we also use them and their genes as tools to study systems of particular interest. This includes the gonads where SOX9 is important for the initiation and maintenance of Sertoli cells in the testis.
Mice are our main experimental model to study sex determination, but the chick is used for evolutionary comparisons, since the initial trigger is different, but downstream effectors are probably the same. Our work also informs the human situation, which when it goes wrong leads to devastating physiological and social consequences for affected individuals.
Figure 2: Pituitary stem cells, which express SOX2, give rise to new endocrine cells upon physiological demand. After removal of the adrenals, negative feedback signals to the pituitary are disrupted and stem cells in the anterior pituitary become activated and proliferate. Lineage tracing experiments using a Cre-activated YFP reporter (green) show that the SOX2-positive stem cells can self renew (green cells), but that their progeny also differentiate to give rise to new ACTH (red) expressing corticotrophs, as shown by double positive cells, arrowheads.
We also study aspects of development of the early embryo, notably of the central nervous system (CNS) and pituitary, and stem cell types, including pluripotent stem cells obtained from very early embryos (ES cells) or from adult cells after reprogramming (iPS cells), and multipotent stem cells from the developing and adult central nervous system and pituitary. The common theme for this research is the role of SOX2 and SOX9 (as well as closely related SOX proteins), which are critical for self-renewal and confer potential to progenitor and stem cells within these systems. We explore how these factors impact on cell fate choices, as well as using them as a route to understand stem cell niches, with the ultimate goal of aiding the treatment of a range of clinical problems, such as stroke, cancer, and defects of pituitary development and function.
