Bowles Lab – Developmental reproductive biology

Research directions

Germ cells, the precursors to sperm and eggs, provide the key to sexual reproduction and continuation of the species. Germ cells are unique in that they are the only cell type in the body capable of undergoing the special reductive cell division, termed meiosis. They also represent an abundant, genuine, stem cell population that can be investigated and manipulated in vivo. Pluripotency of male germ cells must be tightly balanced during embryonic development: sufficient numbers of pluripotent stem cells must be allocated for fertility, but unconstrained pluripotency gives rise to cancer precursors that develop into germ cell tumours of the testis after puberty.

In the Bowles Lab we investigate the role of molecular signaling pathways that control the critical processes of meiosis and germline pluripotency during both normal development (in mice) and in disease (in humans).

Understanding how stem cells control pluripotency versus differentiation is a key problem in the fields of development, reproduction and cancer. Approximately one in nine Australian couples are infertile and testis cancer accounts for more than 60% of cancers diagnosed in young men. Fundamental information regarding key signaling networks that control stem cell pluripotency, gleaned from our in vivo germ cell models, will greatly advance stem cell therapies, fertility restoration or ablation for population control as well as potential cancer prevention and treatment.

Testis and ovaryWe have 3 broad programs of investigation that focus on various aspects of germ cell development:

  1. Sex specific development of fetal germ cells
  2. Germline stem cell identity and function
  3. The genesis of germline tumorigenesis

Research keywords

Germ cells, development, testis, ovary, pluripotency, germ cell cancer

Current collaborations

  • Professor Leendert H.J. Looijenga, Erasmus Medical Center, Rotterdam, The Netherlands
  • Dr Kristian Almstrup, Copenhagen University Hospital, Copenhagen, Denmark
  • Professor Moira O’Bryan, Monash University, Melbourne, Australia

Opportunities for new researchers

Positions are available within each research program for undergraduates, honours students, PhD students, and postdoctoral scientists, and we are happy to entertain new ideas. If you are interested in joining the lab, please contact Jo Bowles.

Current projects

Sex specific development of fetal germ cells

During fetal development, germ cell fate and behaviour is not intrinsically programmed, but instead depends on molecular cues from gonadal somatic cells. In a fetal ovary, germ cells enter meiosis and commit to oogenesis, whereas in a fetal testis, they avoid entry into meiosis and instead undergo mitotic arrest and begin to mature towards spermatogenesis. In mice, these fate decisions occur in the critical window 11.5-13.5 days post coitum (dpc), soon after the germ cells arrive in the nascent gonads.

1.Sex specific development of fetal germ cellsDuring this critical period of germ cell development, we aim to understand:

  • How meiosis is triggered in female germ cells
  • What makes female germ cells capable of responding to Retionic acid
  • How do male germ cells control pluripotency versus differentiation decisions

Germline stem cells

Spermatogonial stem cells (SSCs) generate millions of sperm each day throughout adult life and, therefore, underpin male fertility. Despite their obvious importance, little is known regarding how the SSC population is set aside and regulated. Germ cells are specified during early embryonic development and migrate to and colonise the nascent fetal testis. Although many thousand germ cells take up residence in the testis, only a small number of these will be earmarked as enduring SSCs; the surplus germ cells differentiate during the first wave of spermatogenesis at puberty (~6 days post partum in mice). Both the exact timing and molecular regulation of SSC allocation however, remains unknown.

During late embryonic and early postnatal male germ cell development, we aim to understand:

  • The exact timing of spermatogonial stem cell allocation
  • Molecularly, how are spermatogonial stem cells different from the greater germ cell population  
  • What signalling pathways are involved in spermatogoinal stem cell allocation and maintenance

Germline stem cells

 

The genesis of germline tumorigenes

The most common and deadly form of testis cancer is Type II germ cell cancer, which accounts for ~60% of all malignancies in men aged 20-40, and is rapidly on the increase in industrialised countries. The cell of origin or ‘cancer stem cell’, germ cell neoplasia in situ (GCNIS), is considered to be a germ cell that has failed to differentiate appropriately during embryonic development. After puberty, GCNIS cells that have remained dormant up until that point, invariably transform into either seminoma (SEM) or non-seminoma (N-SEM) germ cell cancer. Seminoma retains a fetal germ cell-like expression profile, while non-seminoma is the more deadly and invasive pluripotent tumour subtype. Understanding the origins of Type II GCC therefore rests on uncovering the mechanisms regulating male germ cell development during fetal life.

In fetal germ cell development, and in human germ cell tumours we aim to:

  • Identify factors that are responsible for restraining germ cell pluripotency
  • Identify developmental signalling pathways that become co-opted in cases of germ cell cancer
  • Develop novel diagnostics/therapeutics for GCNIS and germ cell cancer

The genesis of germline tumorigenes

 

2017

Book chapter

Spiller, Cassy M., Burnet, Guillaume and Bowles, Josephine (2017). Mouse fetal germ cell isolation and culture techniques. In Michael Buszczak (Ed.), Germline stem cells Second edition ed. (pp. 173-183) New York, NY, United States: Humana Press. doi:10.1007/978-1-4939-4017-2_13

Journal article

2016

2015

Book chapter

Bowles, Josephine and Koopman, Peter (2015). Retinoic acid and the control of meiotic initiation. In Pascal Dolle and Karen Niederreither (Ed.), The retinoids: biology, biochemistry, and disease (pp. 383-399) New Jersey, NY, United States: Wiley - Blackwell. doi:10.1002/9781118628003.ch17

Journal article

Lab head

  • Dr Josephine Bowles

    Dr Josephine Bowles

    Senior Lecturer in Biomed Sciences & Research Fellow
    School of Biomedical Sciences

Staff

Students

Find out more about our research environment and how to apply to do a short or long-term research project with us.