THE GLUCOCORTICOID RECEPTOR IS A KEY REGULATOR OF THE DECISION BETWEEN SELF-RENEWAL AND DIFFERENTIATION IN ERYTHROID PROGENITORS

During development and in regenerating tissues such as the bone marrow , progenitor cells constantly need to make decisions between prolifera tion and differentiation, We have used a model system, normal erythroi d progenitors of the chicken, to determine the molecular players invol ved in making this decision, The molecules identified comprised recept or tyrosine kinases (c-Kit and c-ErbB) and members of the nuclear horm one receptor superfamily (thyroid hormone receptor and estrogen recept or), Here we identify the glucocorticoid receptor (GR) as a key regula tor of erythroid progenitor self-renewal (i.e. continuous proliferatio n in the absence of differentiation). In media lacking a GR ligand or containing a GR antagonist, erythroid progenitors failed to self-renew , even if c-Kit, c-ErbB and the estrogen receptor were activated simul taneously, To induce self-renewal, the GR required the continuous pres ence of an activated receptor tyrosine kinase and had to cooperate wit h the estrogen receptor for full activity, Mutant analysis showed that DNA binding and a functional AF-2 transactivation domain are required for proliferation stimulation and differentiation arrest, c-myb was i dentified as a potential target gene of the GR in erythroblasts. It co uld be demonstrated that Delta c-Myb, an activated c-Myb protein, can functionally replace the GR.