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Disorders of sex development

We are investigating embryonic gonad development and abnormalities of this process that cause disease. We use mouse models to better understand the genes and molecular pathways involved in sex determination, and work closely with clinical geneticists to identify causative genes and improve diagnosis.

Disorders of sex development (DSD) occur when there is a mismatch between the phenotypic sex of an individual and their chromosomal sex. We mainly study 46,XY gonadal dysgenesis, in which XY individuals develop as females, by investigating the underlying genetics of this condition in mice.

Collaboration with clinical geneticists to identify testis-determining genes

DSDs can manifest as a range of abnormalities of gonad and genitalia development, from the mild, such as an undescended testis, through to the severe, such as ambiguous external genitalia. Such birth defects, whilst rare, can cause considerable distress, both for the person themselves and for their parents. Around 70% of people born with 46,XY gonadal dysgenesis have no genetic diagnosis available to them, and individuals may only discover they have the condition when problems arise during or after puberty.

We work with clinical geneticists to identify and validate causative genes and improve diagnostic genetic screening. The clinical geneticists we collaborate with sequence and analyse the genomes of DSD patients in order to identify candidate genes which may cause the disorder. We then determine whether or not these genes are actually involved by studying mice with the equivalent gene mutations and knockout mice lacking the gene. By analysing the development of the gonads in these mice, we can determine whether or not the gene is involved in the condition. We then conduct further molecular analyses to determine the effect of the mutation on the gene product and the consequences of this for the differentiating cells of the gonads.

We have previously had a very successful collaboration with a clinician in New York, whom we assisted in identifying mutations in human MAP3K1 that cause 46,XY gonadal dysgenesis. We discovered that Map3k1 is expressed in the mouse embryonic gonad at the time of testis determination, although a lack of the gene causes only minor abnormalities in testis development in mice. Interestingly, loss of a related gene, Map3k4, does cause XY female development in mice. MAP3K1 now forms part of routine diagnostic genetic screens in patients.

Studying the regulation of genes that determine gonad development

From the perspective of developmental biology, sex determination involves the commitment of cell lineages in the embryonic gonad to one of two potential fates - testicular or ovarian. How is this cell fate commitment controlled by sex determining genes? We investigate the role of genes that are required for the development of the mouse testis and the mechanisms by which they determine sex.

Recently we have focussed on the role of mitogen-activated protein kinase (MAPK) molecules and how they control gene activity. This requires an examination of gene expression and the underlying epigenomic mechanisms that control this. The Sry gene on the Y chromosome initiates the development of the embryonic gonads into testes. We are interested in how the expression of Sry is regulated, and how mutations in genes involved in the regulatory pathways we are studying affect Sry and other sex-determining genes.

In particular, we are interested in signalling to the epigenome - how MAPK and related signals establish chromatin states at distinct loci that drive testis development. In addition to using mouse embryonic tissue directly, we are also investigating methods that will allow us to reprogram cells in vitro and provide us with an abundant source of material for the study of the epigenome of the embryonic Sertoli cell, a key cell type of the developing testis.

In recent years we have identified three genes that work together in a pathway to regulate the expression of Sry and commit the gonad to testis development. We are using these as entry points into molecular pathways that will allow us to determine the exact mechanisms by which these molecules control male gonad development.