What Exactly Do We Do?
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. A complex transcriptional network underlies the bipotential state and the process of sex determination; however, antagonism between Fgf/Sox9 and Wnt4/Rspo1/beta-catenin signaling pathways plays a leading role in controlling male or female differentiation. Using a genetic and systems biology approach, we have investigated how Sry, the Y-linked sex-determining gene in mammals, functions to trip the bistable switch toward testis development, and how male vs female pathways are stabilized. A question that is currently at the top of our list is how the early gonad is initially established and how cells in this community co-ordinate their fate decisions.
We are also interested in using the dramatic reorganization of gonadal tissue into testis or ovary morphology as a model for the study of organogenesis. In the past ten years, much of this work has centered on recruitment of the vasculature in XY gonads, and the critical role that endothelial cells play in testis organogenesis. More recently, we have become interested in how the morphology and cell types of the ovary are established, and particularly in how a better understanding of ovary organogenesis can help in the design of therapies for premature ovarian failure.
As a comparative model for sex determination and organogenesis, we investigate the red-eared slider turtle, T. scripta. Curiously, although germ cells arrive in the gonad in a different location, and morphogenesis of the testis and ovary occurs in a completely different manner, the resulting adult testis and ovary structure is very similar. Comparison of the transcriptional network in the turtle and mouse will reveal underlying similarities and differences that control testis or ovary fate commitment and morphological development.
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 spermatogonial stem cell during 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.
Some Current Areas of Interest
- How is cell fate established and maintained during sex determination in the mouse? How are extracellular signals (including diffusible signals and extracellular matrix molecules) coordinated with intracellular pathways that regulate the fate of gonadal cells, and how is this process integrated with proliferation and coordinated across the gonad field?
- How is the primordial follicle pool established during ovary organogenesis? What is the potential of the ovary to repair and recover from damage, and can this potential be harnessed in the clinic?
- How is the population of spermatogonial stem cells established in the testis? What are the somatic and environmental signals that influence the fate of male germ cells and the incidence of testicular tumors?
- What portion of the sex determination network characterized in mouse gonads is conserved in red-eared slider turtles (Trachemys scripta elegans) where sex determination is regulated by temperature? Is there an underlying genetic system in T. scripta? How does temperature intersect the transcriptional network?
- How does the germ cell population in T. scripta establish male or female specific fate from both a molecular and a morphological perspective?