A Conserved Role for Hox Paralog Group 4 in Regulation of Hematopoietic Progenitors
- 1 June 2009
- journal article
- research article
- Published by Mary Ann Liebert Inc in Stem Cells and Development
- Vol. 18 (5), 783-792
- https://doi.org/10.1089/scd.2008.0227
Abstract
Regulatory circuits that control stem cell fate decisions can be identified and understood by manipulating individual regulatory elements genetically. While impractical in the rare somatic stem cells of primary tissue, this approach is feasible in embryonic stem cells differentiated in vitro into the somatic stem cell type of interest. We present an improved highly efficient targeting system allowing genes to be integrated into a predetermined, doxycycline-inducible locus, and corresponding inducible embryonic stem cell lines to be generated rapidly. We apply this system to evaluate a key hematopoietic progenitor cell regulatory element, HoxB4, and its mammalian paralogs, whose effects have not yet been tested in this context. We show that all Hox paralog group 4 members, A4, B4, C4, and D4, have similar effects on hematopoietic stem and progenitor self-renewal in vitro, and thus classify Hox paralog group 4 as promoting self-renewal. Each paralog group 4 member both promotes proliferation and inhibits differentiation, enabling the exponential expansion of hematopoietic progenitors from the c-kit+/CD41+ cell fraction of day 6 murine embryoid bodies. By evaluating a set of deletion mutants we show that sequences in addition to the homeodomain and hexapeptide motif are required for this activity. These results highlight the utility of this expression system to perform functional and structural analyses of genetic regulators of cell fate decisions.Keywords
This publication has 44 references indexed in Scilit:
- Analysis of HSC activity and compensatory Hox gene expression profile in Hoxb cluster mutant fetal liver cellsBlood, 2006
- Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cellsNature Medicine, 2006
- Differential Expression of Novel Potential Regulators in Hematopoietic Stem CellsPLoS Genetics, 2005
- Tie2/Angiopoietin-1 Signaling Regulates Hematopoietic Stem Cell Quiescence in the Bone Marrow NicheCell, 2004
- Hoxb4-deficient mice undergo normal hematopoietic development but exhibit a mild proliferation defect in hematopoietic stem cellsBlood, 2004
- MLL Targets SET Domain Methyltransferase Activity to Hox Gene PromotersMolecular Cell, 2002
- A Stem Cell Molecular SignatureScience, 2002
- Overexpression of HOXB3 in Hematopoietic Cells Causes Defective Lymphoid Development and Progressive MyeloproliferationImmunity, 1997
- Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemiaNature Genetics, 1996
- Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo.Genes & Development, 1995