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Hoxa9/hoxb3/hoxb4 compound null mice display severe hematopoietic defects

Magnusson, Mattias LU ; Brun, Ann LU ; Lawrence, H. Jeffrey and Karlsson, Stefan LU (2007) In Experimental Hematology 35(9). p.1421-1428
Abstract
Obyective. Members of the box family of homeodomain-containing transcription factors, including hoxa9, hoxb3, and hoxb4 play an important role in the regulation of differentiation, proliferation and self-renewal of hematopoietic stem and progenitor cells. Lack-of-function studies using hoxa9, hoxb4, or hoxb3/hoxb4 null mice demonstrate that all these mutations compromise the repopulating ability of hematopoietic stem cells (HSC), implying similar functions of each of these genes in hematopoiesis. Because cross regulation and cooperativity are known features of box proteins, we investigated mice with a compound deficiency in hoxa9, hoxb3 and hoxb4 (hoxa9/b3/b4) for evidence of synergy between these genes in hematopoiesis. Materials and... (More)
Obyective. Members of the box family of homeodomain-containing transcription factors, including hoxa9, hoxb3, and hoxb4 play an important role in the regulation of differentiation, proliferation and self-renewal of hematopoietic stem and progenitor cells. Lack-of-function studies using hoxa9, hoxb4, or hoxb3/hoxb4 null mice demonstrate that all these mutations compromise the repopulating ability of hematopoietic stem cells (HSC), implying similar functions of each of these genes in hematopoiesis. Because cross regulation and cooperativity are known features of box proteins, we investigated mice with a compound deficiency in hoxa9, hoxb3 and hoxb4 (hoxa9/b3/b4) for evidence of synergy between these genes in hematopoiesis. Materials and Methods. Hoxa9/b3/b4 were generated by mating the hoxb3/boxb4 null mice with the hoxa9 null strain and HSC function was measured by competitive repopulating assay and by immunophenotype using fluorescence-activated cell sorting. Results. Our findings demonstrate that the hoxa9/b3/b4 null mice are smaller in body weight, and display a marked reduction in spleen size and cellularity compared to control mice. The numbers of colony-forming unit (CFU)-granulocyte macrophage and CFU-spleen progenitor colonies were normal but hoxa9/b3/b4 null bone marrow contained increased numbers of immunophenotypic HSC (Lin(-), c-kit(+), Sca-1(+), CD150(+)). However the reconstitution defect in hoxa9 null HSC was not enhanced further in the hoxa9/b3/b4 null HSC. Conclusion. These findings demonstrate overlapping functions of hoxa9, hoxb3, and hoxb4 in hernatopoietic cells, and emphasize an important role for these transcription factors for regulation of HSC proliferation. However, none of these box proteins is absolutely essential for generation or maintenance of all major blood lineages. (c) 2007 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Experimental Hematology
volume
35
issue
9
pages
1421 - 1428
publisher
Elsevier
external identifiers
  • wos:000249475500012
  • scopus:34548180591
ISSN
1873-2399
DOI
10.1016/j.exphem.2007.05.011
language
English
LU publication?
yes
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c5d53848-75b1-4b83-8392-bfd571cb7d74 (old id 686618)
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17761289&dopt=Abstract
date added to LUP
2007-12-14 14:54:24
date last changed
2017-10-22 03:43:24
@article{c5d53848-75b1-4b83-8392-bfd571cb7d74,
  abstract     = {Obyective. Members of the box family of homeodomain-containing transcription factors, including hoxa9, hoxb3, and hoxb4 play an important role in the regulation of differentiation, proliferation and self-renewal of hematopoietic stem and progenitor cells. Lack-of-function studies using hoxa9, hoxb4, or hoxb3/hoxb4 null mice demonstrate that all these mutations compromise the repopulating ability of hematopoietic stem cells (HSC), implying similar functions of each of these genes in hematopoiesis. Because cross regulation and cooperativity are known features of box proteins, we investigated mice with a compound deficiency in hoxa9, hoxb3 and hoxb4 (hoxa9/b3/b4) for evidence of synergy between these genes in hematopoiesis. Materials and Methods. Hoxa9/b3/b4 were generated by mating the hoxb3/boxb4 null mice with the hoxa9 null strain and HSC function was measured by competitive repopulating assay and by immunophenotype using fluorescence-activated cell sorting. Results. Our findings demonstrate that the hoxa9/b3/b4 null mice are smaller in body weight, and display a marked reduction in spleen size and cellularity compared to control mice. The numbers of colony-forming unit (CFU)-granulocyte macrophage and CFU-spleen progenitor colonies were normal but hoxa9/b3/b4 null bone marrow contained increased numbers of immunophenotypic HSC (Lin(-), c-kit(+), Sca-1(+), CD150(+)). However the reconstitution defect in hoxa9 null HSC was not enhanced further in the hoxa9/b3/b4 null HSC. Conclusion. These findings demonstrate overlapping functions of hoxa9, hoxb3, and hoxb4 in hernatopoietic cells, and emphasize an important role for these transcription factors for regulation of HSC proliferation. However, none of these box proteins is absolutely essential for generation or maintenance of all major blood lineages. (c) 2007 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.},
  author       = {Magnusson, Mattias and Brun, Ann and Lawrence, H. Jeffrey and Karlsson, Stefan},
  issn         = {1873-2399},
  language     = {eng},
  number       = {9},
  pages        = {1421--1428},
  publisher    = {Elsevier},
  series       = {Experimental Hematology},
  title        = {Hoxa9/hoxb3/hoxb4 compound null mice display severe hematopoietic defects},
  url          = {http://dx.doi.org/10.1016/j.exphem.2007.05.011},
  volume       = {35},
  year         = {2007},
}