Retinoblastoma promotes definitive erythropoiesis by repressing Id2 in fetal liver macrophages

Antonio Iavarone (), Emerson R. King, Xu-Ming Dai, Gustavo Leone, E. Richard Stanley and Anna Lasorella
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Antonio Iavarone: Department of Pathology, College of Physicians and Surgeons of Columbia University
Xu-Ming Dai: Albert Einstein College of Medicine
Gustavo Leone: Immunology and Medical Genetics, The Ohio State University
E. Richard Stanley: Albert Einstein College of Medicine
Anna Lasorella: Department of Pathology, College of Physicians and Surgeons of Columbia University

Nature, 2004, vol. 432, issue 7020, 1040-1045

Abstract: Abstract In mammals, the fetal liver is the first site of definitive erythropoiesis—the generation of mature, enucleated red cells. The functional unit for definitive erythropoiesis is the erythroblastic island, a multicellular structure composed of a central macrophage surrounded by erythroblasts at various stages of differentiation1,2. Targeted disruption of the retinoblastoma (Rb) tumour suppressor gene in the mouse leads to embryonic death caused by failure of erythroblasts to enucleate3,4,5. The erythroid defect has been attributed to loss of Rb in cells that support erythropoiesis, but the identity of these cells is unknown6. Here we show that Rb-deficient embryos carry profound abnormalities of fetal liver macrophages that prevent physical interactions with erythroblasts. In contrast, wild-type macrophages bind Rb-deficient erythroblasts and lead them to terminal differentiation and enucleation. Loss of Id2, a helix–loop–helix protein that mediates the lethality of Rb-deficient embryos7, rescues the defects of Rb-deficient fetal liver macrophages. Rb promotes differentiation of macrophages by opposing the inhibitory functions of Id2 on the transcription factor PU.1, a master regulator of macrophage differentiation. Thus, Rb has a cell autonomous function in fetal liver macrophages, and restrains Id2 in these cells in order to implement definitive erythropoiesis.

Date: 2004
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DOI: 10.1038/nature03068

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