title: Analysis of HSC activity and compensatory Hox gene expression profile in Hoxb cluster mutant fetal liver cells.
abstract: Overexpression of Hoxb4 in bone marrow cells promotes expansion of hematopoietic stem cell (HSC) populations in vivo and in vitro, indicating that this homeoprotein can activate the genetic program that determines self-renewal. However, this function cannot be solely attributed to Hoxb4 because Hoxb4(-/-) mice are viable and have an apparently normal HSC number. Quantitative polymerase chain reaction analysis showed that Hoxb4(-/-) c-Kit+ fetal liver cells expressed moderately higher levels of several Hoxb cluster genes than control cells, raising the possibility that normal HSC activity in Hoxb4(-/-) mice is due to a compensatory up-regulation of other Hoxb genes. In this study, we investigated the competitive repopulation potential of HSCs lacking Hoxb4 alone, or in conjunction with 8 other Hoxb genes. Our results show that Hoxb4(-/-) and Hoxb1-b9 (-/-) fetal liver cells retain full competitive repopulation potential and the ability to regenerate all myeloid and lymphoid lineages. Quantitative Hox gene expression profiling in purified c-Kit+ Hoxb1-b9(-/-) fetal liver cells revealed an interaction between the Hoxa, b, and c clusters with variation in expression levels of Hoxa4,-a11, and -c4.Together, these studies show a complex network of genetic interactions between several Hox genes in primitive hematopoietic cells and demonstrate that HSCs lacking up to 30% of the active Hox genes remain fully competent.
authors.affiliation: Laboratory of Molecular Genetics of Stem cells, Institute for Research in Lmmunology and Cancer (IRIC), Montréal, QC, Canada.
authors.forename: Janet
authors.initials: J
authors.lastname: Bijl
authors.forename: Alexander
authors.initials: A
authors.lastname: Thompson
authors.forename: Ramiro
authors.initials: R
authors.lastname: Ramirez-Solis
authors.forename: Jana
authors.initials: J
authors.lastname: Krosl
authors.forename: David G
authors.initials: DG
authors.lastname: Grier
authors.forename: H Jeffrey
authors.initials: HJ
authors.lastname: Lawrence
authors.forename: Guy
authors.initials: G
authors.lastname: Sauvageau
mesh_terms: D000818:Animals; D002452:Cell Count; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics*; D008099:Liver / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C513262:Hoxb4 protein, mouse; D014157:Transcription Factors