Hoxa9/hoxb3/hoxb4 compound null mice display severe hematopoietic defects.
OBJECTIVE
Members of the hox 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 hox 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.


METHODS
Hoxa9/b3/b4 were generated by mating the hoxb3/hoxb4 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.


CONCLUSIONS
These findings demonstrate overlapping functions of hoxa9, hoxb3, and hoxb4 in hematopoietic cells, and emphasize an important role for these transcription factors for regulation of HSC proliferation. However, none of these hox proteins is absolutely essential for generation or maintenance of all major blood lineages.
Magnusson
Mattias
M
Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine, The Lund Strategic Center for Stem Cell Biology and Cell Therapy, Lund University Hospital, Lund, Sweden.
Brun
Ann C M
AC
Lawrence
H Jeffrey
HJ
Karlsson
Stefan
S
D000818:Animals; D001835:Body Weight; D019070:Cell Lineage; D006413:Hematopoietic System / Q000002:abnormalities* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009929:Organ Size; D013154:Spleen / Q000033:anatomy & histology / Q000166:cytology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D018398:Homeodomain Proteins; C503713:Hoxb3 protein, mouse; C513262:Hoxb4 protein, mouse; D014157:Transcription Factors; C097899:homeobox protein HOXA9