Hoxa cluster genes determine the proliferative activity of adult mouse hematopoietic stem and progenitor cells
| Autor: | Fournier, Marilaine, Kettyle, Laura M.J., Thompson, Alexander, Sauvageau, Guy, Bijl, Janet J. |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| ISSN: | 0006-4971 1528-0020 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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