c-Maf rules the island

In this issue of Blood, Kusakabe et al make a compelling case that the transcription factor c-Maf is critical for erythroblastic island formation and fetal erythropoiesis.¹  The cell adhesion molecule VCAM-1 is a potential mediator of c-Maf activity.

The erythroblastic island was ultrastructurally identified as a common organizational unit of bone marrow more than 50 years ago.²  Erythroblastic islands are composed of erythroblasts, at various stages of maturation, and a central macrophage. The central macrophage supports erythroid cell survival and proliferation through intercellular signaling, and facilitates enucleation.³  Along this line, several molecules have been identified that mediate intercellular attachments and macrophage-erythroblast interactions within the island.^4-6  Still, despite these advances the role of the central macrophage in erythroid development remains somewhat obscure. Kusakabe et al now show that the basic region-leucine zipper transcription factor c-Maf is critical for erythroblastic island formation.^1,6  The macrophage is the site of c-Maf activity, and c-Maf deficiency is associated with severe embryonic anemia and lethality. This study opens a new avenue into the investigation of erythroblastic islands.

Establishing the cell type responsible for a phenotypic effect is challenging and critical in any study of heterotypic intercellular interactions. Kusakabe et al performed mixing experiments with c-Maf–deficient erythroblasts and macrophages that convincingly show that defects in erythroblastic island formation, caused by the loss of c-Maf, reside with the macrophage.¹  However, can the same be said of the embryonic anemia and lethality, or does c-Maf deficiency also have an erythroid cell autonomous effect on development? One approach to address this question is to examine the effect of c-Maf deficiency on erythropoiesis, when it is induced specifically in the macrophage and erythroid lineages; however, this requires a conditional Maf-mutant mouse strain. In lieu of this, 2 other lines of evidence suggest that c-Maf function in macrophages and erythroblastic island formation are required for efficient erythropoiesis. First, c-Maf is expressed in macrophages but not erythroblasts in the fetal liver, which suggests that macrophages are the primary site of c-Maf activity. Second, adult mice transplanted with c-Maf–deficient fetal liver cells do not develop anemia. This experiment shows that there is no cell autonomous requirement for c-Maf in erythroid development, and further implies that erythroblastic island function is most important during fetal development. Alternatively, there may be a fetal-specific requirement for c-Maf in erythroblastic island formation. Finally, consistent with the proposed role of the central macrophage, Kusakabe et al show that survival of mature c-Maf–deficient erythroblasts is defective in vivo.¹  Thus, c-Maf deficiency causes defective macrophage development and impairs erythroid cell survival and development through its effect on the erythroblastic island.

Given that c-Maf is the first transcription factor identified that is important for erythroblastic island function, it raises the question of the relevant targets of c-Maf in macrophages. Here, Kusakabe et al provide evidence that VCAM-1 is one such target. VCAM-1 has a proven role in erythroblastic island formation,⁴  which makes it an excellent candidate for a mediator of c-Maf activity; however, because VCAM-1 is not essential for erythropoiesis, there are likely to be other relevant c-Maf targets.⁷  Known regulators of erythroblastic island formation, such as retinoblastoma and erythroblast-macrophage protein, have been excluded; thus, additional targets of c-Maf are likely to be novel and their identification an important future objective. Beyond the role of macrophages in erythroid development, erythroblastic islands also serve as a paradigm for interactions between hematopoietic cells and their microenvironment. In this regard, the present identification of a transcriptional regulator of erythroblastic island formation may lead to broader insights into the regulation of hematopoiesis.