Mammalian hematopoiesis is based on the activity of multipotent hematopoietic stem cells (HSC) that undergo continuous self-renewal throughout the adult life. The self-renewal represents a unique property of adult HSC, and appears distinct from the proliferation of hematopoietic progenitors or from the initial specification and expansion of embryonic HSC. Despite recent progress, little is known about the molecular mechanisms governing HSC self-renewal. Zfx is a broadly expressed zinc finger-containing transcriptional activator that is highly conserved in vertebrates. Using conditional gene targeting in mice, we demonstrate that Zfx is an essential and specific regulator of HSC self-renewal. The expression of Zfx was elevated in HSC compared to progenitors and differentiated cells. An inducible deletion of Zfx from the adult bone marrow (BM) resulted in the specific loss of the HSC population. The short-term proliferation and lodging of Zfx-deficient HSC in the BM were normal, suggesting a specific defect of long-term self-renewal. The deletion of Zfx in pre-established BM chimeras completely abrogated HSC maintenance as reflected by the rapid loss of HSC contribution to hematopoiesis. Furthermore, a constitutive pan-hematopoietic deletion of Zfx spared embryonic HSC in the fetal liver, yet resulted in the loss of adult BM HSC. In contrast, adult erythromyeloid progenitors or differentiated cells were not affected by the absence of Zfx. Genome-wide expression analysis identified candidate target genes of Zfx, some of which were controlled by Zfx in HSC but not in their differentiated progeny. Finally, several immediate-early and/or stress-inducible genes were upregulated specifically in Zfx-deficient HSC, suggesting that the latter undergo increased stress-related signaling. Thus, functional and gene expression analysis establishes Zfx as a novel specific regulator of adult HSC self-renewal. Further studies of the target genes and pathways controlled by Zfx should provide novel insights into the molecular basis of HSC function.

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