Abstract
Hematopoietic stem cells are both necessary and sufficient to sustain the complete blood system of vertebrates. Here we show that Nfix, a member of the nuclear factor I (Nfi) family of transcription factors, is highly expressed by hematopoietic stem and progenitor cells (HSPCs) of murine adult bone marrow. Although short hairpin RNA-mediated knockdown of Nfix expression in Lineage(-)Sca-1(+)c-Kit(+) HSPCs had no effect on in vitro cell growth or viability, Nfix-depleted HSPCs displayed a significant loss of colony-forming potential, as well as short- and long-term in vivo hematopoietic repopulating activity. Analysis of recipient mice at 4 to 20 days posttransplant revealed that Nfix-depleted HSPCs are established in the bone marrow, but fail to persist due to increased apoptotic cell death. Gene expression profiling of Nfix-depleted HSPCs reveals that loss of Nfix expression in HSPCs is concomitant with a decrease in the expression of multiple genes known to be important for HSPCs survival, such as Erg, Mecom, and Mpl. These data reveal that Nfix is a novel regulator of HSPCs survival posttransplantation and establish a role for Nfi genes in the regulation of this cellular compartment.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult Stem Cells / cytology
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Adult Stem Cells / metabolism*
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Animals
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Antigens, Ly / genetics
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Antigens, Ly / metabolism
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Apoptosis
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Bone Marrow Cells / cytology
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Bone Marrow Cells / metabolism*
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Cell Survival
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Gene Expression Profiling
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Gene Expression Regulation
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Hematopoiesis / genetics*
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Hematopoietic Stem Cell Transplantation
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / metabolism*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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NFI Transcription Factors / deficiency
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NFI Transcription Factors / genetics*
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NFI Transcription Factors / metabolism
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-kit / genetics
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Proto-Oncogene Proteins c-kit / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptors, Thrombopoietin / genetics
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Receptors, Thrombopoietin / metabolism
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Signal Transduction
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Transcription Factors
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Transcriptional Regulator ERG
Substances
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Antigens, Ly
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ERG protein, mouse
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Ly6a protein, mouse
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Membrane Proteins
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Mpl protein, mouse
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NFI Transcription Factors
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Nfix protein, mouse
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Oncogene Proteins
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RNA, Small Interfering
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Receptors, Thrombopoietin
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Transcription Factors
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Transcriptional Regulator ERG
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Proto-Oncogene Proteins c-kit