Retinoblastoma promotes definitive erythropoiesis by repressing Id2 in fetal liver macrophages.
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 differentiation. Targeted disruption of the retinoblastoma (Rb) tumour suppressor gene in the mouse leads to embryonic death caused by failure of erythroblasts to enucleate. The erythroid defect has been attributed to loss of Rb in cells that support erythropoiesis, but the identity of these cells is unknown. 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 embryos, 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.
Iavarone
Antonio
A
Institute for Cancer Genetics, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA. ai2102@columbia.edu
King
Emerson R
ER
Dai
Xu-Ming
XM
Leone
Gustavo
G
Stanley
E Richard
ER
Lasorella
Anna
A
D000818:Animals; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D020964:Embryo Loss / Q000097:blood / Q000378:metabolism / Q000473:pathology; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000502:physiology*; D005333:Fetus / Q000166:cytology*; D017353:Gene Deletion; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2; D008099:Liver / Q000166:cytology* / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012175:Retinoblastoma / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D020298:U937 Cells
D004268:DNA-Binding Proteins; C497450:ID2 protein, human; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D012097:Repressor Proteins; D014157:Transcription Factors