Abstract
The transcription factor PU.1 is required for the development of mature myeloid and lymphoid cells. Due to this essential role and the importance of PU.1 in regulating several signature markers of lymphoid progenitors, its precise function in early lymphopoiesis has been difficult to define. Here, we demonstrate that PU.1 was required for efficient generation of lymphoid-primed multipotent progenitors (LMPPs) from hematopoietic stem cells and was essential for the subsequent formation of common lymphoid progenitors (CLPs). By contrast, further differentiation into the B-cell lineage was independent of PU.1. Examination of the transcriptional changes in conditional progenitors revealed that PU.1 activates lymphoid genes in LMPPs, while repressing genes normally expressed in neutrophils. These data identify PU.1 as a critical regulator of lymphoid priming and the transition between LMPPs and CLPs.
Highlights
Hematopoietic stem cells (HSCs) are responsible for the development of all mature blood cell types
Previous studies have reported that LSK cells and common lymphoid progenitors (CLPs) express relatively high amounts of PU.1 [15, 16, 46]
It has long been known that PU.1 is required for lymphocyte formation from either the fetal or adult HSCs, the function of PU.1 in lymphopoiesis and the exact point at which it is required has proven more elusive
Summary
Hematopoietic stem cells (HSCs) are responsible for the development of all mature blood cell types. The LSK population includes lymphoid-primed multipotent progenitors (LMPPs) whose potential is skewed toward lymphocyte and myeloid differentiation [2]. LMPPs are defined by a characteristically high cell surface concentration of Flt and express of a number of lymphoid transcripts, a process termed lymphoid priming. The expression of a GFP reporter expressed from the Rag locus can be used to identify a population termed the early lymphoid progenitor (ELP) that overlaps with the LMPP [3]. The common lymphoid progenitor (CLP) is developmentally downstream of the LMPP and its potential appears largely restricted to the lymphoid lineages, in vivo, if not in vitro [4,5,6]. CLPs upregulate expression of IL-7Rα, while maintaining Flt and Rag1/GFP [7, 8]. BLPs differentiate directly into committed B cells through the concerted activity of E2A, EBF1, and Pax5 [10]
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