%0 Journal Article
%T PU.1 and Haematopoietic Cell Fate: Dosage Matters
%A Ka Sin Mak
%A Alister P. W. Funnell
%A Richard C. M. Pearson
%A Merlin Crossley
%J International Journal of Cell Biology
%D 2011
%I Hindawi Publishing Corporation
%R 10.1155/2011/808524
%X The ETS family transcription factor PU.1 is a key regulator of haematopoietic differentiation. Its expression is dynamically controlled throughout haematopoiesis in order to direct appropriate lineage specification. Elucidating the biological role of PU.1 has proved challenging. This paper will discuss how a range of experiments in cell lines and mutant and transgenic mouse models have enhanced our knowledge of the mechanisms by which PU.1 drives lineage-specific differentiation during haematopoiesis. 1. Introduction Haematopoiesis is a lifelong process that generates the range of blood cell types that exhibit distinct and specialised functions. Transcription factors play a critical role in this complex and highly orchestrated process, directing multipotent haematopoietic stem cells (HSCs) towards lineage commitment by regulating lineage-specific gene expression, proliferation, and differentiation. The ETS family member PU.1 is one such transcription factor The PU.1 gene was first identified as a proviral integration site for the spleen focus forming virus (SFFV) in erythroleukaemias [1]. SFFV integration in the PU.1 locus leads to increased PU.1 transcription and subsequent erythroleukaemic transformation. It has since emerged that PU.1 is one of the major haematopoietic regulators, with a particular role in directing differentiation within the myeloid and lymphoid pathways [2]. Several PU.1 null and mutant mouse lines have been generated and exhibit varied phenotypes depending on the nature of PU.1 defect [3]. PU.1 knockout mice succumb to neonatal death and show a marked lack of myeloid cells, T and B cells [4, 5]. Erythropoiesis is also altered in the foetal livers of PU.1 null mice with erythroid progenitors displaying reduced self-renewal capacity and a propensity to differentiate prematurely [6]. PU.1 is thus crucial in directing many facets of haematopoiesis and concordant with this, its expression fluctuates dynamically in the various haematopoietic differentiation pathways (Figure 1). Importantly, the regulation of differentiation by PU.1 is not merely via a ˇ°presence or absence of expressionˇ± mechanism but by a dose-dependent effect. For instance, the expression of PU.1 is low in long-term reconstituting (LT)-HSCs but rises as these progenitors become more lineage restricted and form precursor cells known as common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs). Upon further lineage differentiation and maturation, PU.1 is expressed at varied levels in mature blood cells, with higher levels found in macrophages than B cells
%U http://www.hindawi.com/journals/ijcb/2011/808524/