The biology of sex determination and how patterning decisions are made during organ development.
The Capel laboratory is interested in the biology of sex determination, and the basic questions it raises about how patterning decisions are made during organ development. Unlike most organs whose fate is pre-determined, the gonad arises as a bipotential primordium that can chose to follow one of two developmental pathways. ‘Primary sex determination’ refers to the decision within the gonad to develop as a testis or ovary, and involves initial cell fate decisions coordinated with a dramatic reorganization of the tissue into testis or ovary morphology. In mammals, the fate of the gonad is controlled by a gene on the Y chromosome, Sry, which tips the balance of underlying signaling pathways. Currently the lab is using systems biology approaches to achieve a better understanding of the global transcriptional network that regulates the fate of the mammalian gonad. We have defined a fine timecourse of gene expression and are combining this with a DNase Hypersensitivity map to predict gene regulatory interactions in this transcriptional cascade. Transcriptome investigations are also underway to determine whether underlying antagonistic signals and feedback reinforcement loops identified in mammals are conserved in other vertebrates such as red eared slider turtles, where sex determination is regulated by the temperature of egg incubation.
Other research in the lab is focused on the morphological reorganization of the cells in the gonad into testis or ovarian structure. The laboratory has pioneered live imaging to explore the architectural patterning of the testis, focusing on the role of the vasculature and the de novo organization of testis cord structures. A key outcome of testis organogenesis is the establishment of the germline stem cell niche inside testis cords. Efforts are centered on understanding how the intracellular program in germ cells, in combination with regulation from the niche within the gonad, lead to the transition of germ cells from a pluripotent state into pro-spermatogonia. This question is addressed through investigation of Dnd1Ter mutants, a classic mouse mutant in which germ cells do not successfully navigate this transition, but instead undergo a transformation event, and give rise to germ cell tumors.