Cellules souches et homéostasie tissulaire
Mots-clésStem cells, Proliferation, Differentiation, Development, Cancer
We are using the stem cells in the adult intestine of Drosophila to uncover general mechanisms controlling stem cells and their differentiated daughter progeny. Our work takes advantage of the sophisticated genetic tools available in Drosophila and high-resolution confocal imaging to investigate the cell biology of the intestine.
Stem cells are essential for development and continued maintenance of tissues and organs. They are characterized by their ability to self-renew as well as to produce differentiated progeny. Understanding the dual capacity of self-renewal and differentiation is an important aim of developmental biology, regenerative medicine, and also has implications for cancer biology.
Regulation of stem cells occurs at many levels: cell intrinsic factors as well as extrinsic signals from the surrounding cells and environment may modulate cell division, stem cell maintenance, and the differentiation process. The aim of work in our group is to identify mechanisms important for these processes and ultimately to understand how they function collectively to promote homeostasis of a tissue. To do so, we are using a simplified model system, the Drosophila midgut (Figure 1). The adult Drosophila midgut intestinal stem cells (ISCs) proliferate to provide differentiated cells over the adult lifetime and also have the capacity to respond rapidly to damage occurring in the gut due to pathogens or abrasion.
Understanding cell fate specification
One of our aims is to understand cell intrinsic signalling required for ISC and daughter cell fate. We are investigating how the Notch signalling pathway controls the fine balance of cell types in the intestine. We found that a modulator of Notch signalling is specifically required for commitment of the ISC daughter cell (EB), thereby acting to limit the number of stem cells. This modulator, however, is completely dispensable for Notch-mediated differentiation of the EB. Our data suggest that a high-threshold Notch signalling barrier must be surmounted in order for proper commitment to occur, whereas differentiation can occur properly with low threshold signalling. We are currently investigating the nature of this barrier, the temporal control of fate decisions, and trying to assess dynamic Notch signalling in this system.
Identifying novel genes controlling stem and daughter cells
We have also taken genetic and genomic approaches to gain broader insight into control of ISCs. Using an EMS-based forward genetic screen, we identified genes required to limit stem cell number and proliferation, control stem cell maintenance, and regulate differentiated daughter fate. We are currently using molecular and genetic approaches to further investigate the roles of these genes in stem cell biology. In parallel, we have taken a genomic approach to identify RNAs that are differentially expressed in the ISC, ee and EC cells and are investigating their potential as regulators and stem cell specific markers. Using these two complementary approaches, we hope to identify both regulatory genes and cellular mechanisms controlling stem and differentiated cells.