We study how stem cells interpret signals from their environment to compete with their neighbours and choose to self-renew or differentiate.
This leads us to examine how stem cell behaviour is affected by signalling, how the cell cycle rate influences competitiveness, and how differentiation is induced and coordinated across the tissue.
Niche signals and competitiveness
We have identified 3 major conserved signalling pathways that control the competitive ability of cyst stem cells (CySCs) in the testis, these are Hedgehog (Hh), Hippo (Hpo) and Ras/MAPK. Importantly, Ras/MAPK acts in a very similar manner in Drosophila CySCs and in mouse intestinal stem cells, suggesting our work will help understand fundamental stem cell behaviours. Ras gain of function leads to intestinal tumours, and the first step involves the mutant stem cell out-competing neighbouring wild type cells.
We use live imaging to follow stem cell replacement dynamics and study how these signals affect stem cell behaviour. We are also using large-scale sequencing approaches to find transcriptional targets of each signal, and find genes that could identify competitive stem cells.
Cell cycle progression and competitive behaviour
Stem cells that proliferate faster out-compete their neighbours and colonise the niche. How the cell cycle rate affects this competitive ability is not understood.
Using live imaging, we are studying what happens to individual stem cells before, during and after cell division, and using that information to understand how the cell cycle length affects competitive behaviour. We are using genetics to clonally accelerate or disrupt cell cycle progression in single stem cells and observe how their dynamics are affected.
Leaving the niche : stem cell behaviour during early differentiation
Just like self-renewal and competing to remain in the niche, differentiation is an active process that requires coordination across a tissue and active signalling. We identified a signal that promotes differentiation. This is the PI3K/Tor pathway, the major regulator of cellular growth.
We are filming the early steps of CySC differentiation to understand what cellular changes take place as cells leave the niche and how the multiple lineages in the tissue are coordinated. We are also exploring the targets of Tor activity in differentiating cells.