Nfix is a novel regulator of murine hematopoietic stem and progenitor cell survival

Holmfeldt, Per; Pardieck, Jennifer; Saulsberry, Anjelica C.; Nandakumar, Satish K.; Finkelstein, David; Gray, John T.; Persons, Derek A.; McKinney‐Freeman, Shannon

doi:10.1182/blood-2013-04-493973

Cited by 42 publications

(68 citation statements)

References 34 publications

(25 reference statements)

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“…In addition, NFIX balances the hematopoietic stem cell (HSPC) survival and apoptosis (Holmfeldt et al, 2013). Functional studies show that NFIX expression is activated by Pax7 in fetal muscles, which activates transcription of fetal specific genes and represses embryonic genes such as slow myosin (Messina et al, 2010;Heng et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Novel alternative splice variants of NFIX and their diverse mRNA expression patterns in dairy goat

Zhang

Zhou

Pan

et al. 2015

Gene

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Section: Introductionmentioning

confidence: 99%

Novel alternative splice variants of NFIX and their diverse mRNA expression patterns in dairy goat

Zhang

Zhou

Pan

et al. 2015

Gene

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“…Furthermore, a transcriptome-wide approach revealed that Nfia induces an eythroid transcriptional program in both CD34 + and leukaemic K562 cells [6]. Nfix knockout mice die postnatally around p21 and have brain, intestine, and skeleton malformations [7,8] and Nfix deficient HSPCs fail to persist in long-term bone marrow engraftment upon transplantation [9]. Recently Nfix was shown to be one of 36 regulatory factors with relatively restricted expression in HSCs, that contributed towards converting a committed B cell to a myeloid cell [10].…”

Section: Introductionmentioning

confidence: 99%

NFIX expression critically modulates early B lymphopoiesis and myelopoiesis

Keeshan

O’Connor

Campos

et al. 2013

Experimental Hematology

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The commitment of stem and progenitor cells toward specific hematopoietic lineages is tightly controlled by a number of transcription factors that regulate differentiation programs via the expression of lineage restricting genes. Nuclear factor one (NFI) transcription factors are important in regulating hematopoiesis and here we report an important physiological role of NFIX in B-and myeloid lineage commitment and differentiation. We demonstrate that NFIX acts as a regulator of lineage specification in the haematopoietic system and the expression of Nfix was transcriptionally downregulated as B cells commit and differentiate, whilst maintained in myeloid progenitor cells. Ectopic Nfix expression in vivo blocked early B cell development stage, coincident with the stage of its downregulation. Furthermore, loss of Nfix resulted in the perturbation of myeloid and lymphoid cell differentiation, and a skewing of gene expression involved in lineage fate determination. Nfix was able to promote myeloid differentiation of total bone marrow cells under B cell specific culture conditions but not when expressed in the hematopoietic stem cell (HSPC), consistent with its role in HSPC survival. The lineage choice determined by Nfix correlated with transcriptional changes in a number of genes, such as E2A, C/EBP, and Id genes. These data highlight a novel and critical role for NFIX transcription factor in hematopoiesis and in lineage specification.

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“…However, studies employing conditional knockout strategies and/or in vitro models have begun to uncover NFI function in these cellular populations. Intriguingly, these studies suggest that, in adult tissue, NFI factors play a contrasting role to that during development, serving to promote quiescence and/or survival of stem cells, rather than their differentiation (Chang et al, 2013;Holmfeldt et al, 2013;Martynoga et al, 2013). , 1999).…”

Section: Genetic Redundancy Of Nfis During Developmentmentioning

confidence: 99%

“…No increase in transcript levels within HFSCs relative to progeny (Tumbar et al, 2004 (Chang et al, 2013;Holmfeldt et al, 2013;Martynoga et al, 2013 it is a strong possibility that inactivating mutations in Nfi genes will be identified in developmental based cancers. Indeed, as discussed in this review, there are a number of recent studies that have shown a potential role for inactivating mutations in NFIs in driving tumorigenesis in medulloblastoma, the most common childhood brain cancer (Wu et al, 2012;Genovesi et al, 2013;Lastowska et al, 2013).…”

Section: Nfix Promotes Survival Of Hematopoietic Stem and Progenitor mentioning

confidence: 99%

“…This proposal was based primarily on two studies, one performed in the skin stem cell niche (Chang et al, 2013), and the other in the haematopoietic system (Holmfeldt et al, 2013). In both these studies, deletion of Nfix (haematopoietic system) or Nfib (skin stem cell niche) from adult stem cells led to increased proliferation and subsequently the depletion of the stem cell pool, suggesting that NFIs were mediating quiescence in these populations.…”

Section: Nfix Is Not Essential For Maintaining the Long-term Quiescenmentioning

confidence: 99%

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The function of NFIX during developmental and adult neurogenesis

Harris¹

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Understanding the transcription factor proteins that control the biology of neural stem cells during embryogenesis provides insight into brain development as well as neurodevelopmental disorders.Likewise, studying the function of transcription factors in adult neural stem cells allows us to appreciate the dynamics of these cells and their contribution to normal cognitive function. It also provides a knowledge base so as to one day harness the activity of adult neural stem cells to treat degenerative conditions of the nervous system.One family of transcription factors key to brain development are the Nuclear Factor Ones (NFIs).Comprised of four members in mammals (NFIA, NFIB, NFIC and NFIX) these proteins promote both neuronal and glial differentiation during mouse forebrain development, and in general, appear to have a highly similar function. This thesis addressed two outstanding questions regarding the function of one these proteins, NFIX, in mouse neural stem cell biology. The first question concerned refining our understanding of NFIX function during forebrain development by determining, which stage of neuron differentiation, from a stem cell to a mature neuron, is The second question I addressed in this thesis, was that if NFI proteins are so important for regulating neural stem cell biology during brain development, then do they also regulate adult neural stem cell biology? I addressed this question by breeding inducible, conditional mice to allow for deletion of Nfix from adult hippocampal neural stem cells and separately, immature neurons. I found that NFIX is essential for adult-borne neuron differentiation, so that in the absence of NFIX, mature neurons are not generated and behavioural deficits ensue. Mechanistically, we found that NFIX is essential for primary dendrite formation, and that without NFIX a proportion of adult hippocampal progenitors switch fate to become oligodendrocytes or aberrantly express increased levels of oligodendrocyte mRNA. In addition to demonstrating the absolute requirement of the NFIX protein for the generation of adult-borne neurons, these findings reveal the surprising tri-

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Nfix is a novel regulator of murine hematopoietic stem and progenitor cell survival

Abstract: Key Points HSPCs fail to persist in the bone marrow of lethally irradiated recipients in the absence of Nfix. Nfix-deficient HSPCs display increased apoptosis during ex vivo culture and in recipient marrow.

Cited by 42 publications

References 34 publications

Novel alternative splice variants of NFIX and their diverse mRNA expression patterns in dairy goat

Novel alternative splice variants of NFIX and their diverse mRNA expression patterns in dairy goat

NFIX expression critically modulates early B lymphopoiesis and myelopoiesis

The function of NFIX during developmental and adult neurogenesis

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