| First Author | Dolznig H | Year | 2002 |
| Journal | Curr Biol | Volume | 12 |
| Issue | 13 | Pages | 1076-85 |
| PubMed ID | 12121614 | Mgi Jnum | J:77819 |
| Mgi Id | MGI:2182673 | Doi | 10.1016/s0960-9822(02)00930-2 |
| Citation | Dolznig H, et al. (2002) Apoptosis protection by the epo target bcl-x(l) allows factor-independent differentiation of primary erythroblasts. Curr Biol 12(13):1076-85 |
| abstractText | BACKGROUND: Erythropoietin (Epo) is required for correct execution of the erythroid differentiation program. Erythropoiesis requires Bcl-X(L), a major late target of Epo-receptor signaling. Mice lacking Bcl-X(L) die around embryonic age E12.5, forming normal erythroid progenitors but lacking functional red cells. Recently, serum-free culture conditions for expansion of murine red cell progenitors were developed, yielding cells capable of in vivo-like terminal differentiation into enucleated erythrocytes, in response to Epo/insulin. Here we address whether Epo function during terminal maturation involves a cytokine-independent 'default program,' requiring only apoptosis inhibition through Epo-dependent upregulation of Bcl-X(L).RESULTS: Exogenous expression of Bcl-X(L) or Bcl-2 in primary murine erythroblasts or clonal erythroblast lines derived from p53(-/-) mice allowed these cells to undergo terminal erythroid maturation, in the complete absence of cytokines. A potential autocrine Epo loop was ruled out by respective neutralizing antibodies. Importantly, sustained proliferation of Bcl-X(L)-expressing immature erythroblasts still required respective factors (Epo, stem cell factor [SCF], and the glucocorticoid receptor ligand dexamethasone [Dex]). Epo-independent differentiation in these Bcl-X(L)- or Bcl-2-expressing, primary erythroblasts was thus triggered by removal of the renewal factors SCF and Dex. This initiated the maturation-specific expression cascade of erythroid transcription factors, followed by differentiation divisions (characterized by a short G1 phase and decrease in cell size), hemoglobin accumulation, and enucleation.CONCLUSIONS: During erythroid maturation, Epo regulates red cell numbers via apoptosis inhibition, caused by Epo-dependent upregulation of the antiapoptotic protein Bcl-X(L). This allows 'default' terminal differentiation of apoptosis-protected, committed erythroblasts, independent of any exogenous signals. |
