What Exactly Do We Do?
Unlike most organs whose fate is pre-determined, the gonad arises as a bipotential primordium that chooses to follow one of two developmental pathways. ‘Gonadal sex determination’ refers to the primary decision within gonadal cells to develop as a testis or ovary. Using genetic and systems biology approaches, we have investigated how Sry, the Y-linked sex-determining gene in mammals, functions to tip the bistable switch toward testis development. Questions currently at the top of our list are how the early gonad is initially established, how cells in the gonad community co-ordinate their fate, and how fate is maintained through epigenetic mechanisms.
Evolutionarily, sex determination a very plastic process. As a comparative model for sex determination, we investigate the red-eared slider turtle, T. scripta. In this species, the temperature of egg incubation controls gonadal sex determination. We are very interested in determining whether there are underlying similarities in the transcriptional network between mice and turtles, and we have begun to unravel the longstanding puzzle of how temperature influences the genetic pathway.
Because of its unique bipotential nature, the gonad is an ideal model of organogenesis. We use the dramatic reorganization of gonadal tissue into either testis or ovary morphology as a model for the study of organogenesis. Based on our knowledge of testis and ovary development, we are exploring the ability of the testis and ovary to regenerate and repair after damage.
Other work in the lab focuses on the interactions between germ cells and somatic cells in testis and ovary development. We are particularly interested in the transition from primordial germ cell to oogonia or spermatogonial stem cell during ovary and
testis development. This transition involves a period of cell cycle arrest during which the pluripotent genome is stabilized. We are very interested in the signals from the somatic environment that control this critical developmental transition and in the process within germ cells.
Experimental approaches in the lab include the use of molecular and biochemical techniques, advanced imaging methods, null mutant mice, transgenic reporter mice, organ culture/tissue recombination assays, mouse genetics and genomics, and systems biology/bioinformatics tools.
Some Current Areas of Interest
- How is cell fate established, coordinated across the gonad field, and maintained during sex determination in the mouse? How is this process integrated with proliferation?
- What portion of the gonadal sex determination network characterized in mice is conserved in red-eared slider turtles (Trachemys scripta elegans), where sex determination is regulated by temperature? How does temperature intersect the genetic pathway?
- How is the RNA-binding protein DND1 involved in establishment of spermatogonial stem cells in the testis? What are the somatic and environmental signals that influence the fate of male germ cells and the incidence of testicular tumors?
- How is the primordial follicle pool established during ovary development? What is the potential of the ovary to repair and recover from damage, and can this potential be harnessed in the clinic?
- Do Sertoli cells in the adult testis have regenerative capacity? Can defective Sertoli cells be replaced in situ?