Position title: Associate Professor, Comparative Biosciences
Phone: School of Medicine & Public Health
- Lab Webpage:
- Jorgensen Lab
The Jorgensen lab uses cell and molecular biology tools to identify genes that are sexually dimorphic during sex differentiation, characterize their functional significance, and finally, understand how they are regulated. Currently, we are focusing on two genes: steroidogenic factor 1 (Sf1) and Iroquois homeobox factor 3 (Irx3).
Disruptions in cell-cell interactions and signaling during fetal development can result in obvious birth defects, but more subtle deficiencies are increasingly being recognized as manifesting in diseases that are not recognized until much later in life. My laboratory’s investigations into female and male gonad development are inspired by the quest to understand the fetal basis of sex-specific adult diseases in reproductive endocrinology. Our interest in female gonad development is focused on formation of the unique cellular niche, the follicle, which ensures survival and maturation of the female gamete. We discovered a cluster of homeobox transcription factors that are expressed during ovary development whose disruption results in follicle failure and oocyte death, classic components of premature ovarian failure, a devastating disease in adult females. Our interest in male gonad development is centered on local regulation of androgen synthesis. Defective androgen synthesis or activity during fetal development is emerging as a component of adult male infertility and decreased virility. Historically, local control of androgenesis was thought to be unique to the developing testis; however, aggressive forms of prostate cancer are now also known to acquire this capacity. Since this discovery, we have parlayed our tools and knowledge of fetal testis androgen synthesis to prostate cancer and demonstrated that prostate cancer cells use similar mechanisms to stimulate androgen production that fuels deadly castration resistant prostate cancer. The major goals of my research have been to discover local cell-cell interactions and molecular mechanisms that are used to establish the nascent ovarian follicle niche, control the onset and maintenance of fetal testosterone synthesis, and stimulate the acquisition of steroidogenic activity within rogue cancer cells.
Female Gonad Development
Several years ago, we discovered sexually dimorphic expression of the Iroquois homeobox transcription factor, Irx3, in developing gonads. Since then, we have learned that 2 of 6 Iroquois family members, Irx3 and Irx5 (heretofore referred to as Irx3/5), exhibit similar spatial and temporal expression patterns that correspond to significant events of ovarian development. These data prompted us to explore the hypothesis that Irx3/5 play an important role in ovary development and follicle formation. My laboratory tested this hypothesis using genetic mouse models with global Irx3/5 deletion including the Fused Toes model (6 deleted genes: Irx3,-5,-6, Fts, Fto, Ftm) and Irx3-/-;Irx5GFP/GFP double knockout mice (Irx3-/- and Irx5-/- single knockouts were fertile). Evaluation of ovaries from these models showed that Irx3/5 are dispensable for ovary and follicle formation; however, nascent primordial follicles fail to thrive and oocytes die within days of follicle formation. Closer examination pointed to disruption of communication networks that facilitate germ-somatic cell communication within germline cysts and new follicles. New preliminary data suggest that IRX3/5 regulate gap junction genes, Gja1 and -5 (connexins 43, 40), among other cell-cell interactors. Our studies highlight IRX3/5 as new factors that mediate critical somatic-germ cell communication and suggest that the very first interactions between these cells within germline cysts and primordial follicles establish granulosa cell and oocyte identities that are required to preserve follicle and oocyte health.
Male Gonad Development & Local Androgen Synthesis
Fetal Testis Synthesized Testosterone
Despite their essential role in differentiation of males, fetal Leydig cells are poorly understood because of 1) their small population size; 2) their rapidly changing biology within developing testes; and 3) the lack of fetal Leydig cell lines. To break down these barriers, we collaborated with Dr. David Beebe’s bioengineering laboratory and utilized genetic mouse models to generate primary fetal testis culture systems that mimic physiologically relevant cell-cell interactions on a microscale. As a result, we can now successfully culture fetal Leydig cells within microfluidic chambers in both mixed and pure populations. In addition, to investigate regulation of genes within the developing gonad, we established a technique using microinjection and electroporation to transfect fetal gonad explants. Using this technique along with fetal gonad chromatin immunoprecipitation, we identified transcription factor binding elements within the proximal promoter of SF1 that govern sex- and time-specific gene expression. This has made significant contributions to collaborative studies to understand gene regulation during testis development. Finally, our studies utilizing genetic mouse models have uncovered integral relationships between Desert Hedgehog signaling, one of its downstream transcription factors, GLI3, and SF1 in regulating fetal androgen synthesis. Our research using Gli3-/- mice suggests that GLI3 transduces critical activation signals to support upregulation of Sf1, steroidogenic enzyme expression, and testosterone production. Together, our studies have provided significant tools to advance the study of fetal Leydig cells and have identified specific factors that regulate SF1 and affect testosterone production.
Aggressive Castration Resistant Prostate Cancer Cells Synthesize Steroids
Fetal development and cancer are two times when cells deviate from their controlled mechanisms of growth and differentiation. Concurrent with our fetal testis work, we discovered that SF1, which is not normally found in the prostate, is expressed in late stage, aggressive prostate cancers. Using in vitro culture and in vivo xenograft systems, we found that SF1 stimulates new steroid synthesis and increases proliferation to fuel deadly tumor growth. Our studies implicate normal developmental and endocrinological roles of SF1 in aberrant steroid production within rogue prostate cancer cells, thereby illuminating a potential new drug target.