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Retinoblastoma promotes definitive erythropoiesis by repressing Id2 in fetal liver macrophages. Nature 2004 Dec 23;432(7020):1040-5

Date

12/24/2004

Pubmed ID

15616565

DOI

10.1038/nature03068

Scopus ID

2-s2.0-11144248047 (requires institutional sign-in at Scopus site)   124 Citations

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 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.

Author List

Iavarone A, King ER, Dai XM, Leone G, Stanley ER, Lasorella A

Author

Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
DNA-Binding Proteins
Embryo Loss
Erythroblasts
Erythropoiesis
Fetus
Gene Deletion
Humans
Inhibitor of Differentiation Protein 2
Liver
Macrophages
Mice
Mice, Knockout
Repressor Proteins
Retinoblastoma
Transcription Factors
U937 Cells