Title: Molecular Genetics of Sex Determination, the Sox Gene Family and Stem Cell Biology
Funder: The Francis Crick Institute

Abstract: 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, which 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 one topic of our research. In addition to typical processes involved in organ development, cells of the gonad have an additional choice to make: to become cells typical of testes or ovaries. In mammals, this decision usually depends on the presence or absence of the Y chromosome gene Sry, which encodes a transcription factor, SRY. This is 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. These genes are autosomal, except for Sry and Sox3 (which is X-linked). The role of several of these genes is a recurrent theme in our research, although we also use them as tools to study systems of particular interest. This includes the gonads, where SOX9 is important for the initiation and maintenance of Sertoli cells, and several stem cell types, where SOX2 and SOX9 help confer their properties. 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. Indeed, we collaborate with groups studying patients, helping to characterise mutations involved in Disorders of Sex Differentiation (DSDs). We are also developing novel methods that might allow treatments and not just better diagnosis, We also study aspects of development, notably of the 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 specific 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. Again, while mice are the main experimental model, our research informs the clinic and vice versa. In addition to better diagnosis and informed management of patients, our work may eventually contribute to treatments. In terms of methodology, we use whatever will get us an answer, but rely heavily on genetic approaches, as well as techniques of molecular biology, embryology, imaging, cell and organoid culture, and some tissue engineering.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL;RENAL AND UROGENITAL