Atsushi Iwama

The transcription factor PU.1 (Spi-1) is a well-characterized regulator of myeloid and lymphoid development. However, its role in mature functional cells is poorly studied. Here we report the characterization of the novel murine gene pDP4 (PU.1 difference product 4), which is absent from fetal livers of PU.1-deficient mice. pDP4 is transcribed as a single 3.2-kb mRNA with a 1518-base pair open reading frame encoded by 5 exons on chromosome 14. pDP4 expression is strongest in small intestine and bone marrow, in which it is expressed predominately in mature neutrophils. Interestingly, however, pDP4 expression is markedly down-regulated in neutrophils of the peripheral blood and peritoneum. The pDP4 gene encodes a secreted 57-kDa glycoprotein with an olfactomedin-like C-terminus. PU.1 binds to a functional site within the pDP4 promoter, and pDP4 expression in myeloid cells is strictly dependent on PU.1 and the presence of this site. In conclusion, we have identified a novel PU.1-regulated extracellular glycoprotein of the olfactomedin-like family with a possible role in neutrophilic trafficking. (Blood. 2004;103:4294-4301)

Myeloid progenitor cells give rise to a variety of progenies including dendritic cells. However, the mechanism controlling the diversification of myeloid progenitors into each progeny is largely unknown. PU.1 and CCAAT/enhancing binding protein (C/EBP) family transcription factors have been characterized as key regulators for the development and function of the myeloid system. However, the roles of C/EBP transcription factors have not been fully identified because of functional redundancy among family members. Using high titer–retroviral infection, we demonstrate that a dominant-negative C/EBP completely blocked the granulocyte–macrophage commitment of human myeloid progenitors. Alternatively, Langerhans cell (LC) commitment was markedly facilitated in the absence of tumor necrosis factor (TNF)α, a strong inducer of LC development, whereas expression of wild-type C/EBP in myeloid progenitors promoted granulocytic differentiation, and completely inhibited TNFα-dependent LC development. On the other hand, expression of wild-type PU.1 in myeloid progenitors triggered LC development in the absence of TNFα, and its instructive effect was canceled by coexpressed C/EBP. Our findings establish reciprocal roles for C/EBP and PU.1 in LC development, and provide new insight into the molecular mechanism of LC development, which has not yet been well characterized.