title: Hoxa cluster genes determine the proliferative activity of adult mouse hematopoietic stem and progenitor cells.
abstract: Determination of defined roles for endogenous homeobox (Hox) genes in adult hematopoietic stem and progenitor cell (HSPC) activity has been hampered by a combination of embryonic defects and functional redundancy. Here we show that conditional homozygous deletion of the Hoxa cluster (Hoxa(-/-)) results in a marked reduction of adult HSPC activity, both in vitro and in vivo. Specifically, proliferation of Hoxa(-/-) HSPCs is reduced compared with wild-type (WT) cells in vitro and they are less competitive in vivo. Notably, the loss of Hoxa genes had little impact on HSPC differentiation. Comparative RNA sequencing analyses of Hoxa(-/-) and WT hematopoietic stem cells (CD150(+)/CD48(-)/Lineage(-)/c-kit(+)/Sca-1(+)) identified a large number of differentially expressed genes, three of which (Nr4a3, Col1a1, and Hnf4a) showed >10-fold reduced levels. Engineered overexpression of Hoxa9 in Hoxa(-/-) HSPCs resulted in partial phenotypic rescue in vivo with associated recovery in expression of a large proportion of deregulated genes. Together, these results provide definitive evidence linking Hoxa gene expression to proliferation of adult HSPCs.
authors.affiliation: Maisonneuve-Rosemont Hospital Research Center, Montreal, QC, Canada; Department of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, QC, Canada;
authors.forename: Charles-Étienne
authors.initials: CÉ
authors.lastname: Lebert-Ghali
authors.affiliation: Maisonneuve-Rosemont Hospital Research Center, Montreal, QC, Canada; Department of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, QC, Canada;
authors.forename: Marilaine
authors.initials: M
authors.lastname: Fournier
authors.affiliation: Center for Cancer Research and Cell Biology, Queen's University, Belfast, United Kingdom;
authors.forename: Laura
authors.initials: L
authors.lastname: Kettyle
authors.affiliation: Center for Cancer Research and Cell Biology, Queen's University, Belfast, United Kingdom;
authors.forename: Alexander
authors.initials: A
authors.lastname: Thompson
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada; and Department of Medicine, University of Montreal, Montreal, QC, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Sauvageau
authors.affiliation: Maisonneuve-Rosemont Hospital Research Center, Montreal, QC, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada; and.
authors.forename: Janet J
authors.identifier: http://orcid.org/0000-0003-1436-3075
authors.initials: JJ
authors.lastname: Bijl
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D000090602:Collagen Type I, alpha 1 Chain; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D018398:Homeodomain Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; C490411:Nr4a3 protein, mouse; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; C088144:HoxA protein