Stem Cell Genetics

Identification of factors that regulate stem cell development in Drosophila and mice

Stem cells are the key to organ regeneration and tumour growth

Many differentiated but renewable cell types in vertebrates are derived from relatively small populations of dedicated precursors, or stem cells. The ability to replenish differentiated cells depends on the continued survival and proliferation of their respective stem cell populations.  Stem cells are not only important for regeneration of healthy tissues but also play a key role in pathogenesis.  Recent studies have demonstrated that all cells in solid tumo`urs do not play equal roles but
a small fraction of cells, the so-called cancer stem cells, contribute to the unlimited growth of the tumour and re-occurrence after tumour resection. If we are to realise the goals of re-programming tissue differentiation, growing organs for transplantation in vitro, regeneration of damaged organs in vivo and targeted effective treatments for cancer it is essential that we understand the molecules and mechanisms that stem cells utilise for renewal and differentiation.

Drosophila and mouse organs – complimentary models of stem cell function

The identification of mechanisms that regulate asymmetric division, daughter cell mitotic amplification and stem cell differentiation have been difficult to ascertain.  These types of studies benefit greatly from the analysis of simple, genetically tractable systems.  For these reasons we have chosen to focus on two stem cell niches in Drosophila and mouse (male germ line and intestinal) as models for stem cell systems. A rosette of germline stem cells (expressing a Snail family transcriptional repressor, green) can be observed surrounding the somatic stem cell niche in the Drosophila

Project SupervisorProjects

Professor Gary Hime

Project 1: Analysing the role of transcriptional regulators in Drosophila and mouse stem cells (in conjunction with Assoc. Prof. Helen Abud, Monash University)

We have shown that transcriptional regulators of epithelial to mesenchymal transition are required in diverse stem cell populations. This role has been conserved through evolution of animals as these proteins can be found in stem cells from Drosophila to mouse.  This project involves using CRISPR and genetically modified Drosophila or mouse intestinal organoid cultures to identify how these proteins regulate stem cell numbers and control the production of differentiated  
progeny cells. See Horvay et al (2015), Voog et al (2014) and Horvay et al (2011).

Project 2: Identification of novel regulators of stem cell differentiation

We have conducted genetic screens which have identified new mutations that affect the ability of Drosophila male germline stem cells to differentiate. This project will involve genetic analysis and DNA sequencing to identify genes associated with specific mutations and phenotypic characterization of the mutant to determine the mechanism affecting stem cell differentiation. See Dominado et al (2016) and Monk et al (2010).

Project 3: Stem cell competition

If a mutation in a cell signaling pathway occurs in a stem cell can that cell outcompete other stem cells and result in the entire stem cell pool of an organ being derived from that single cell? What effects might this have on the ability of the stem cell to differentiate and produce functional cells? This project will use the genetic tools available in Drosophila to generate single mutant stem cells and follow their progeny. We will assay what proportion of the stem cell pool is generated from the mutant stem cell over time and if the mutant cells can produce functional differentiated progeny.

Project 4: How does alternative splicing regulate stem cell maintenance

Regulators of RNA splicing can lead to different isoforms of genes being expressed in stem cells. This project will use genetic methods, immunostaining and confocal microscopy to determine if different splice forms of signalling molecules affect stem cell maintenance and differentiation.

Project 5: Characterisation of the regenerative capacity of salivary glands

Adult salivary glands are important for transmission of parasites from mosquito and tick vectors but the cell biology of these glands has been poorly characterised. This project will use Drosophila as a genetic model to understand salivary gland development and regeneration.

Project 6: Transgenerational modification of survival efficacy in the advent of climate change

There are several lines of evidence that parental health is strongly linked to offspring health outcomes. In humans and mammalian models, non-genetic factors established to impact on offspring include traumatic/chronic stress and imbalanced diets. However, metabolic consequences pertaining to thermoregulation are ill-defined. Extreme climate events are becoming more frequent with documented consequences for the reproduction and population sizes of a variety of insects globally. Here, we will use the drosophila model to study how transient exposures to temperature spikes can cause a transgenerational shift in the survival probability of subsequent generations. Using distinct genetic strains with differential heat resistance  , we seek to identify precise molecular mechanisms regulation in form of transgenerational inheritance. We will also be investigating how heat stress impacts on the male reproductive system to initiate the transgenerational response.