Mechanisms of foetal urogenital system development

CentresCentre for Reproductive HealthEndocrinology and immunophysiology > Mechanisms of foetal urogenital system development

Research Project:
Mechanisms of foetal urogenital system development


Research Group:
Endocrinology and immunophysiology

Project Leader:
Mai Sarraj, email: mai.sarraj@mimr-phi.org

Summary:

We are studying the roles of particular genes in the formation of the foetal ovary, testis, and kidney. Information gained from these studies is integral to the development of better therapies and treatments for reproductive tract disease in humans.

Description:

While the causes of reproductive tract disease are not well-understood, genetic abnormalities are considered a major risk factor. With multiple genes interacting to regulate reproductive health and fertility, the task of determining the underlying genetic causes of reproductive disease in humans is complex and challenging. The study of transgenic and knockout mice allows scientists to dissect out the roles of particular genes in the development and progression of diseases. Information gained from these studies is integral to the development of better therapies and treatments.

Our work focuses on the betaglycan gene, which encodes a cell-surface co-receptor that increases the sensitivity of cells to TGFβ and inhibin, two factors that regulate reproductive biology. We have previously deleted the betaglycan gene in mice, which resulted in a variety of birth defects, and roles for betaglycan in the growth and development of foetal organs were uncovered.

Our recent work focuses on discovering the role of this receptor in the foetal and adult urogenital system, in particular in the ovary, testis, and kidney. Defects in the development of these organs impact upon their health and functional capacity in adulthood, and a major goal of our research is to uncover the key developmental processes involved in determining adult reproductive capacity.

We recently established a culture system to enable further study of the role of betaglycan and TGFb in ovary and testis development. Using this system we have showed that loss of TGFb/ betaglycan function results in abnormal migration (movement) and aggregation (clumping) of the key support cells of the developing sperm and egg. These defects may affect fertility in adult men and women.

We have also been exploring the impacts of betaglycan levels on kidney development. Our research has shown that betaglycan levels must be tightly controlled for optimal kidney formation. A partial or total loss of betaglycan from kidney cells results in changes to foetal kidney function and structure. This is thought to have long-ranging implications, adversely affecting adult kidney function and contributing to kidney-related diseases such as renal hypertension.

We use a combination of molecular and histochemical techniques to understand the regulatory processes that govern foetal development, including transcriptional profiling using high-throughput quantitative real time PCR, wholemount and section in situ hybridisation and immunocytochemistry, explant culture, and confocal microscopy.

Funding:

  • National Health and Medical Research Council
  • Heart Foundation
  • Ian Potter Foundation

 

Outcomes:

  • Demonstrated that the betaglycan gene is expressed differentially in the foetal, neonatal, and adult ovary and testis, suggesting multiple sex-specific roles for betaglycan in gonadal differentiation and maturation.
  • Established in betaglycan null mice that betaglycan is essential for the proper development of testis structure and for the proper functioning of the testis endocrine cells, the Leydig cells
  • Showed that betaglycan was required for normal foetal kidney formation and function

 

Selected Publications:

Aleman-Muench G, Mendoza V, Stenvers K, Garcia-Zepeda EA, Lopez-Casillas F, Raman C, Soldevila G (2012) Betaglycan (TβRIII) is expressed in the thymus and regulates T cell development by protecting thymocytes from apoptosis. PLoS ONE 7(8): e44217.

Walker KA, Sims-Lucas S, Caruana G, Cullen-McEwen L, Li J, Sarraj MA, Bertram JF, Stenvers KL (2011) Betaglycan is required for the establishment of nephron endowment in the mouse. PLoS ONE 6(4):e18723.

Sarraj MA, Escalona RM, Umbers A, Chua HK, Small C, Griswold M, Loveland K, Findlay JK, Stenvers KL (2010) Fetal testis dysgenesis and compromised Leydig cell function in Tgfbr3 (betaglycan) knockout mice. Biol Reprod, 82(1):153-62.

Sarraj MA, Chua HK, Umbers A, Loveland KL, Findlay JK, and Stenvers KL. (2007) Differential expression of TGFBR3 (betaglycan) in mouse ovary and testis during gonadogenesis. Growth Factors. 25(5):334-45.

Stenvers, KL, Tursky, ML, Harder, KW, Kountouri, N, Amatayakul-Chantler, S, Grail, D, Small, C, Weinberg, RA, Sizeland, A and Zhu, HJ (2003) Defective heart and liver development and reduced TGF-β2 sensitivity in transforming growth factor-beta type III receptor-deficient embryos. Mol. Cell. Biol. 23(12): 4371-85

Updated: 19/9/12