Life Sciences Division

Regulating the production of red blood cells: bringing balance under control

CEA

Janice Haney-Carr. The body has massive needs for red blood cells. To meet these needs, around 100 million RBCs have to be produced every single day. Research in progress at the iMETI (Institute of emerging diseases and innovative therapy, CEA/Fontenay-aux-Roses) is steadily delivering insights on the mechanisms involved in what has to be a tightly-governed regulatory system controlling RBC production. iMETI teams have demonstrated the pivotal role of a protein called GATA-1 in controlling the balance between erythroid precursors and RBCs. They pinpointed the involvement of an interaction between GATA-1 and two essential partners: the pRb/E2F-2 complex and the protein FOG-1.

In addition to providing fundamental insight on normal and disease-state erythroid differentiation, this research opens up exiting perspectives for screening similar mechanisms in other body tissues that express members of the GATA family. These findings have just been published online in PLoS Biology.

Red blood cell production through erythropoiesis [1] requires a delicate balance between three biological processes (figure): 

proliferation: process through which cells multiply without changing phenotype [2];
differentiation: mechanism that enables the cells to acquire a new phenotype;
apoptosis: mechanism of programmed cell death.

Taken individually, each of these biological processes has been charted, analyzed and decoded, but the overarching mechanisms coordinating them have yet to be explored.
 
For close-on 30 years, researchers have known that the protein GATA-1 plays an important role as transcription factor activating the expression of the majority of protein families found in red blood cells (globins, blood group proteins, etc.). The transcriptional activity of GATA-1 is modulated by protein cofactor [3] FOG-1.
 
Research produced at the iMETI has revealed a new function for the GATA-1/FOG-1 couple in controlling proliferation-differentiation balance. This control is exerted through the interaction between GATA-1 and the complex formed by the proteins pRb, which is encoded by a retinoblastoma tumour suppressor gene, and E2F-2. This interaction inhibits erythroid precursor proliferation and enables normal erythroid differentiation. The iMETI teams have also demonstrated in vitro that the FOG-1 can dislocate GATA-1 from the pRb/E2F-2 complex and induce a shift in the proliferation–differentiation balance towards proliferation.
 

Their work has cemented two important points. One – it has confirmed the intrinsic (and hotly disputed) role of pRb in erythropoiesis. Two – it has deciphered the molecular mechanisms underpinning the interaction between these proteins that orchestrate a fine-grained control over the balance between proliferation and differentiation during late-stage erythropoiesis. GATA-1 therefore clearly plays a central role in various different physiological processes, while the FOG-1 cofactor is one of the rheostats regulating the balancing act between erythroid proliferation and differentiation. These findings should deepen our understanding of the mechanisms involved in certain GATA-1 gene mutation-related diseases that lead to either severe anaemia or myelodysplastic syndrome [4].

1 Erythropoiesis is a series of processes through which red blood cells (erythrocytes) are produced from hematopoietic stem cells inside bone marrow.
2 Phenotype: the cell phenotype is the set of observable characteristics of a given cell.
3 Cofactor: a molecule that is required for another protein’s biological activity.
4¨Myelodysplastic syndrome: a hematopoietic stem cell disorder characterized by the abnormal production of certain blood cell types.