Our laboratory uses the mouse as an animal model, and our research explores two main areas:
Genetic basis of susceptibility to infectious diseases
The clinical outcome of infectious diseases in humans and domestic animals is determined by complex interactions between the pathogen and the host genomes, under the influence of environmental and stochastic factors. The discovery of mechanisms of host defence that are crucial to effective and protective responses to infections is a major medical challenge. Experimental standardised infection of mice from controlled matings between inbred strains offers a complementary approach to genetic dissection of resistance to infections in humans. This approach eliminates several sources of environmental variance hence making easier the identification of mechanisms of host resistance to microbial infection.
The overall approach consists in identifying differences amongst inbred strains in susceptibility to a given pathogen, and isolate the genetic components involved in this difference. We take advantage of mouse strains derived from wild-caught progenitors because such ‘wild’ strains exhibit higher genetic diversity than classical laboratory strains, derived from Mus musculus. We are also using the Collaborative Cross as an additional source of genetic and phenotypic variation. We work on real life-threatening pathogens in collaboration with Institut Pasteur teams, such as Yersinia pestis bacillus – the Plague agent -, Rift Valley fever virus, Salmonella Typhimurium and Dengue and Zika viruses.
We have discovered that mice derived from another Mus species, Mus spretus, are exceptionally resistant to fully virulent Y. pestis strains compared to classical laboratory mice. We have also shown that this resistance is controlled by at least four genetic factors. We have extended this approach to study resistance to Rift Valley fever and identified a wild-derived inbred strain that carries a selective defect that does not enable these mice to successfully combat infection with the Rift Valley fever virus. Using a quantitative linkage analysis, we have identified major loci on chromosomes 2, 5, and 11 that control the outcome of Rift Valley fever disease. Current work focuses on the identification of genes, cellular pathways, and mechanisms involved in resistance to these infections.
The biology of self-renewal and differentiation of stem cells
Stem cells are capable of both generating identical progeny, and producing transient amplifying cells (TA-cells) committed to differentiate. Regulation of the number of stem cells, TA-cells and differentiated cells is a crucial problem in multicellular organisms. Indeed, tissues and organs in the embryo and in the adult rely heavily on homeostasis, where, as cells die accidentally or naturally, they are replenished. Defects in stem cell self-renewal and differentiation may lead to lineage disappearance or cancer. Many of the features that govern the behaviour of stem cells both in the embryo and in the adult remain unknown.
In the early embryo, we study the genetic determinants and signaling pathways regulating stem cell specification and maintenance. Using deep-sequencing based miRNA profiling, we have recently provided evidence that miRNA changes are important for the developmental maturation of naive pluripotent stem cells. Our objective is to identify novel factors involved in the acquisition and maintenance of embryonic and extra-embryonic identities.
In the adult, we have shown that Notchless plays a key role in the maintenance of hematopoietic and intestinal stem cells. We have also revealed unsuspected differences in ribosome biogenesis that distinguish stem cells from restricted progenitor populations.