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PMID:20610818

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Citation

Pajerowski, AG, Shapiro, MJ, Gwin, K, Sundsbak, R, Nelson-Holte, M, Medina, K and Shapiro, VS (2010) Adult hematopoietic stem cells require NKAP for maintenance and survival. Blood 116:2684-93

Abstract

Steady-state hematopoiesis is sustained through differentiation balanced with proliferation and self-renewal of hematopoietic stem cells (HSCs). Disruption of this balance can lead to hematopoietic failure, as hematopoietic differentiation without self-renewal leads to loss of the HSC pool. We find that conditional knockout mice that delete the transcriptional repressor NKAP in HSCs and all hematopoietic lineages during embryonic development exhibit perinatal lethality and abrogation of hematopoiesis as demonstrated by multilineage defects in lymphocyte, granulocyte, erythrocyte and megakaryocyte development. Inducible deletion of NKAP in adult mice leads to lethality within 2 weeks, at which point hematopoiesis in the bone marrow has halted and HSCs have disappeared. This hematopoietic failure and lethality is cell intrinsic, as radiation chimeras reconstituted with inducible Mx1-cre NKAP conditional knockout bone marrow also succumb with a similar time course. Even in the context of a completely normal bone marrow environment using mixed radiation chimeras, NKAP deletion results in HSC failure. NKAP deletion leads to decreased proliferation and increased apoptosis of HSCs, which is likely due to increased expression of the cyclin-dependent kinase inhibitors p21Cip1/Waf1 and p19Ink4d. These data establish NKAP as one of a very small number of transcriptional regulators that is absolutely required for adult HSC maintenance and survival.

Links

PubMed PMC2974581 Online version:10.1182/blood-2010-02-268391

Keywords

Adult Stem Cells/cytology; Adult Stem Cells/metabolism; Animals; Animals, Newborn; Cell Proliferation; Cell Survival/genetics; Cell Survival/physiology; Co-Repressor Proteins/genetics; Co-Repressor Proteins/metabolism; Cyclin-Dependent Kinase Inhibitor p21/genetics; Female; Hematopoiesis/genetics; Hematopoiesis/physiology; Hematopoietic Stem Cells/cytology; Hematopoietic Stem Cells/metabolism; Male; Mice; Mice, Knockout; Mice, Transgenic; NF-kappa B/metabolism; Pregnancy; Promoter Regions, Genetic; RNA, Messenger/genetics; RNA, Messenger/metabolism; Radiation Chimera

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:NKAP

acts_upstream_of_or_within

GO:0030097: hemopoiesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3765313,MGI:MGI:4839023

P

  • results_in_development_of:(EMAPA:32760)|results_in_development_of:(EMAPA:16846)

Seeded From UniProt

complete

MOUSE:NKAP

acts_upstream_of_or_within

GO:0019827: stem cell population maintenance

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3765313,MGI:MGI:4839023

P

Seeded From UniProt

complete

MOUSE:NKAP

acts_upstream_of_or_within

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2176073,MGI:MGI:4839023

P

Seeded From UniProt

complete

MOUSE:NKAP

acts_upstream_of_or_within

GO:0033077: T cell differentiation in thymus

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3765313,MGI:MGI:4839023

P

  • occurs_in:(EMAPA:18768)

Seeded From UniProt

complete

MOUSE:NKAP

acts_upstream_of_or_within

GO:0030851: granulocyte differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2176073,MGI:MGI:4839023

P

Seeded From UniProt

complete

MOUSE:NKAP

enables

GO:0031490: chromatin DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:NKAP

acts_upstream_of_or_within

GO:0071425: hematopoietic stem cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2176073,MGI:MGI:4839023

P

Seeded From UniProt

complete


See also

References

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