Developmental haematopoiesis group
This group belongs to the group: From haematopoietic stem cell to megakaryocyte
Our aim is to better define the events leading to the edification of the haematopoietic system, with a particular focus on its early steps. Indeed, the changes in the mechanisms sustaining the emergence and maintenance of haematopoietic progenitors, as well as changes in the regulation of haematopoiesis, which occur during embryonic life seem to be reactivated during the development of various pediatric haemopathies or in the predisposition to leukaemia. It is therefore essential to improve our knowledge of the development steps leading to adult type haematopoiesis.
During ontogeny, blood cells are sequentially produced in various sites, first in the yolk sac (YS), then in the fetal liver and the thymus, and finally in the bone marrow. Haematopoietic progenitors generated in the YS provide the first blood cells of the embryo. However, this production is transient, and the maintenance of haematopoiesis during the fetal life depends on a second and independent generation event, that leads to the production of HSC in the aorta region. It is nowadays accepted that these HSC are responsible for the colonisation of haematopoietic rudiments and the development of lifelong haematopoiesis
Even though the knowledge of developmental haematopoiesis tremendously progressed over the last decades, major unsolved questions in the field concern the regulation of the potential of haematopoietic progenitors from the YS and aorta region, as well as their contribution to further developmental steps.
Role of the transcription factor Lyl-1
Lyl-1, a basic helix-loop-helix (bHLH) transcription factor related to Tal-1/SCL, is involved in chromosomal translocations leading to T-cell acute lymphoblastic leukaemia. The disruption of lyl-1 bHLH domain or the deletion of the full coding sequence leads to an impaired self-renewal ability of adult HSC. While the requirement of Tal-1/SCL for HP generation during developmental haematopoiesis is well established, the role played by Lyl-1 is still unknown. Using Lyl-1lacZ mice in which the bHLH domain is disrupted, we observed that Lyl-1 and Tal-1/SCL expression pattern during development is highly overlapping, notably in newly generated HSC. Moreover, Lyl-1 invalidation led to two defects that affect both YS-haematopoiesis and the production of HSC in the aorta region.
Our main current project is to better characterise the developmental defects resulting from Lyl-1 inactivation, through a thorough analysis of the contribution of Lyl-1 expressing cells to the developing embryo.
Regulation of progenitors potential during developmental haematopoiesis
Whereas the function of RNA interference is beginning to be unraveled in the ES cell model at early stages of mesoderm determination, as well as during adult haematopoiesis, there is currently little information on the involvement of RNA interference at stages when the haematopoietic system is established.
Using a murine model (developed by S. Germain, Collège de France) in which Dicer is constitutively deleted in the progenitors during the whole process of haematopoietic development, we analyse how RNA interference contributes to the regulation of developmental haematopoiesis.