Understanding the Mechanisms of Human Gonadal Development – MGonDev

Gonad development in mammals depends on a cell fate decision that occurs in a bipotential somatic cell to commit to Sertoli (male) or granulosa (female) cells. This switch is a classic but poorly understood question in biology. Data suggest that mammalian sex-determination (SD) involves complex mutually antagonistic genetic interactions of testis- and ovary-determining pathways. SD is achieved by suppression of the alternate fate and maintained in adulthood by mutually antagonistic double-repressive pathway(s) and serves as a paradigm for cell fate choice during development. This project aims to understand the processes that are involved in human SD and how errors in this process lead to a switch in cell identity by multiple parallel approaches. These include exome/genome sequencing patients with errors in SD to identify genetic factors involved, developing innovative and novel complimentary cellular models based on unique mutations that change cell/organ identity in order to define the mechanisms involved and finally to use these data to develop mouse models. As well as providing fundamental insights into cell fate choice during SD, this study will provide novel pathophysiological perspectives and clinically useful diagnostic markers for development of future diagnostic tools and interact fully with major EU and international consortia, which have interests in the fundamental biology, clinical and social aspects of SD and rare diseases.