Germline Stem Cell Laboratory
Doctor Robin Hobbs
Australian Regenerative Medicine Institute (ARMI)
Level 1, Bldg 75
The germline stem cell laboratory is headed by Dr Robin M. Hobbs who is a pioneering young researcher in the germ cell field. He has recently relocated from Beth Israel Deaconess Medical Center associated with Harvard Medical School in Boston and has a joint appointment with MISCL and the Australian Regenerative Medicine Institute (ARMI).
The main focus of the laboratory is to define critical mechanisms underlying adult stem cell function through use of germline stem cells from the mouse testis as a model system. Maintenance of a wide array of adult tissues is dependent on a resident population of stem cells that must self-renew and generate differentiating daughter cells. The appropriate control of stem cell self-renewal and differentiation is critical for tissue homeostasis while disruption of the balance between these processes can contribute to tissue degeneration or cancer.
In adult testis, there is a population of germline stem/progenitor cells (known as spermatogonial progenitor cells or SPCs) that are required for life-long production of differentiating germ cells and spermatozoa. A handful of cell intrinsic factors are known to be involved in SPC maintenance, foremost amongst which is the transcription factor Promyelocytic Leukemia Zinc Finger (Plzf). A major focus of the group is to define downstream targets of Plzf in SPCs and their role in SPC function. This is achieved by using a combination of mouse genetics, flow cytometry analysis and in vitro SPC culture techniques. The principal aim of this research is to identify and characterize novel molecular mechanisms underlying adult stem cell function.
Transcription factor networks controlling germline progenitor function.
We have characterized a direct functional interaction between Plzf and the transcription factor Spalt-like 4 (Sall4), which belongs to a family of related factors with critical developmental roles. Through conditional deletion of Sall4 within the mouse germ lineage we have identified essential roles for this factor at distinct stages of male germline development. An ongoing research focus of the group is to define Sall4 targets in SPCs and to assess the importance of Plzf-Sall4 crosstalk to embryonic development and in other stem cell systems.
Translational regulation of germline progenitor differentiation.
The mTORC1 signalling complex is a key regulator of mRNA translation within the cell and its activity is perturbed in many pathological conditions including cancer. Activation of mTORC1 promotes mRNA translation in general but can also drive translation of specific sets of mRNAs. We have found that Plzf promotes SPC self-renewal through its ability to indirectly inhibit mTORC1. We aim to assess how mTORC1-driven changes in translation, cell growth and metabolism affect SPC function.
Restriction of germline progenitor potency.
Cultured SPCs can convert spontaneously at low frequency to pluripotent embryonic-like stem cells (germline cell-derived pluripotent stem cells; GPSCs) but the mechanisms driving this reprogramming process are unknown. An interest of the group is to identify those factors controlling SPC to GPSC conversion with a view to improving the efficiency of GPSC formation. This alternative source of pluripotent stem cells can have great relevance for regenerative medicine.
Hobbs, R.M. et al. Functional Antagonism between Sall4 and Plzf Defines Germline Progenitors. Cell Stem Cell 10, 284-98 (2012).
Hobbs, R.M., Seandel, M., Falciatori, I., Rafii, S. & Pandolfi, P.P. Plzf regulates germline progenitor self-renewal by opposing mTORC1. Cell 142, 468-79 (2010).
Fagoonee, S., Hobbs, R.M. et al. Generation of functional hepatocytes from mouse germ line cell-derived pluripotent stem cells in vitro. Stem cells and development 19, 1183-1194 (2010).
Seandel, M. et al. Generation of functional multipotent adult stem cells from GPR125+ germline progenitors. Nature 449, 346-50 (2007).
Costoya, J.A. and Hobbs, R.M. et al. Essential role of Plzf in maintenance of spermatogonial stem cells. Nat Genet 36, 653-9 (2004).