Hoxa cluster genes determine the proliferative activity of adult mouse hematopoietic stem and progenitor cells

Lebert-Ghali, Charles-Étienne and Fournier, Marilaine and Kettyle, Laura M.J. and Thompson, Alexander and Sauvageau, Guy and Bijl, Janet J. (2016) Hoxa cluster genes determine the proliferative activity of adult mouse hematopoietic stem and progenitor cells. Blood, 127 (1). pp. 87-90. ISSN 1528-0020

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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.

Item Type: Article
Additional Information: This research was originally published in Blood. Charles-Étienne Lebert-Ghali, Marilaine Fournier, Laura Kettyle, Alexander Thompson, Guy Sauvageau and Janet J. Bijl Blood 2016 127: pp. 87-90; doi:10.1182/blood-2015-02-626390 © the American Society of Hematology.
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine
Identification Number: 10.1182/blood-2015-02-626390
Depositing User: Eprints, Support
Date Deposited: 09 Nov 2016 11:17
Last Modified: 13 Oct 2017 16:56
URI: http://eprints.nottingham.ac.uk/id/eprint/38605

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