Bcl11a Controls Flt3 Expression in Early Hematopoietic Progenitors and Is Required for pDC Development In Vivo

Xiaodi Wu,Theresa L Murphy,Pentao Liu,Ansuman T Satpathy,Wumesh Kc,Kenneth M Murphy,Susan Kovats

doi:10.1371/journal.pone.0064800

Abstract

Bcl11a is a transcription factor known to regulate lymphoid and erythroid development. Recent bioinformatic analysis of global gene expression patterns has suggested a role for Bcl11a in the development of dendritic cell (DC) lineages. We tested this hypothesis by analyzing the development of DC and other lineages in Bcl11a −/− mice. We found that Bcl11a was required for expression of IL-7 receptor (IL-7R) and Flt3 in early hematopoietic progenitor cells. In addition, we found severely decreased numbers of plasmacytoid dendritic cells (pDCs) in Bcl11a −/− fetal livers and in the bone marrow of Bcl11a −/− fetal liver chimeras. Moreover, Bcl11a −/− cells showed severely impaired in vitro development of Flt3L-derived pDCs and classical DCs (cDCs). In contrast, we found normal in vitro development of DCs from Bcl11a −/− fetal liver cells treated with GM-CSF. These results suggest that the persistent cDC development observed in Bcl11a −/− fetal liver chimeras reflects derivation from a Bcl11a- and Flt3-independent pathway in vivo.

Highlights

Dendritic cells (DCs), comprising classical dendritic cell (DC) and plasmacytoid DCs, develop from a common DC progenitor (CDP) residing in the bone marrow (BM); unlike myeloid progenitors at earlier stages of development, CDPs have excluded monocyte and macrophage potential but give rise to all DC subsets at the clonal level [1,2,3,4]
Bcl11a is expressed at similar levels in the hematopoietic stem cell (HSC), multipotent progenitor (MPP), common lymphoid progenitor (CLP), common myeloid progenitor (CMP), and megakaryocyte–erythroid progenitor (MEP) [16]
Four to six weeks after transfer, donor-derived Bcl11a2/2 BM showed decreased frequencies of LSK cells, CLPs, and CDPs but comparable frequencies of granulocyte-macrophage progenitor (GMP) and MEPs relative to donorderived wild type (WT) BM (Fig. 2A, B); within the LSK fraction, donorderived Bcl11a2/2 BM showed a greater proportion of CD150+ cells than did donor-derived WT BM, corresponding to a decrease in the overall frequency of the more differentiated CD150– population (Fig. 2C)

Summary

Introduction

Dendritic cells (DCs), comprising classical DCs (cDCs) and plasmacytoid DCs (pDCs), develop from a common DC progenitor (CDP) residing in the bone marrow (BM); unlike myeloid progenitors at earlier stages of development, CDPs have excluded monocyte and macrophage potential but give rise to all DC subsets at the clonal level [1,2,3,4]. Several transcription factors that act broadly in hematopoiesis are known to regulate the development of all DCs, including Ikaros [5,6], PU.1 [7,8], and Gfi1 [9]. Transcription factors that regulate specific subsets of DCs have been reported. Other factors identified in this analysis include Irf, Bcl11a, and Runx. Other factors identified in this analysis include Irf, Bcl11a, and Runx2 It has been demonstrated in the setting of competitive BM reconstitution that Irf promotes the development of all DC subsets [21], even though Irf82/2 mice in other settings do not show defects in CD4+ cDC development [12,13]. Whether a similar early role in DC development could be identified for another factor such as Bcl11a

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Conclusion