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Musashi 2 is a regulator of the hematopoietic stem cell compartment identified by a retroviral insertion screen and knockout mice

ABSTRACT: We have used a retroviral integration screen to search for novel genes that regulate hematopoietic stem cell (HSC) function. One of the genes that conferred HSC dominance when overexpressed due to an adjacent retroviral insertion was Musashi 2 (Msi2), an RNA binding protein that can act as a translational inhibitor. A gene trap mouse model that inactivates the gene shows that Msi2 is more highly expressed in long term (LT) and short term (ST) HSCs as well as in lymphoid myeloid primed progenitors (LMPPs), but much less in intermediate progenitors and mature cells. Mice lacking Msi2 are fully viable up to more than a year but exhibit severe defects in primitive precursors, most significantly a reduction in the number of ST-HSCs and LMPPs and a decrease of leukocyte numbers, effects that are exacerbated with age. Cell cycle and gene expression analyses suggest that the main hematopoietic defect in Msi2 defective mice consists in a decreased proliferation capacity of ST-HSCs and LMPPs. In addition, HSCs lacking Msi2 are severely impaired in competitive repopulation experiments, being overgrown by wild type cells even when mutant cells were provided in excess. Our data indicate that Msi2 maintains the stem cell compartment mainly by regulating the proliferation of primitive progenitors downstream of LT-HSCs. RNA from 2 different cell populations (LSK cells and KIT+ cells) were analyzed for both wildtype and Msi2-/- null samples. Two technical replicates were analyzed for the KIT+ samples and three technical replicates were analyzed for the LSK samples.

ORGANISM(S): Mus musculus

SUBMITTER: Eric Kallin

PROVIDER: E-GEOD-29432 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Musashi 2 is a regulator of the hematopoietic stem cell compartment identified by a retroviral insertion screen and knockout mice

Project description:We have used a retroviral integration screen to search for novel genes that regulate hematopoietic stem cell (HSC) function. One of the genes that conferred HSC dominance when overexpressed due to an adjacent retroviral insertion was Musashi 2 (Msi2), an RNA binding protein that can act as a translational inhibitor. A gene trap mouse model that inactivates the gene shows that Msi2 is more highly expressed in long term (LT) and short term (ST) HSCs as well as in lymphoid myeloid primed progenitors (LMPPs), but much less in intermediate progenitors and mature cells. Mice lacking Msi2 are fully viable up to more than a year but exhibit severe defects in primitive precursors, most significantly a reduction in the number of ST-HSCs and LMPPs and a decrease of leukocyte numbers, effects that are exacerbated with age. Cell cycle and gene expression analyses suggest that the main hematopoietic defect in Msi2 defective mice consists in a decreased proliferation capacity of ST-HSCs and LMPPs. In addition, HSCs lacking Msi2 are severely impaired in competitive repopulation experiments, being overgrown by wild type cells even when mutant cells were provided in excess. Our data indicate that Msi2 maintains the stem cell compartment mainly by regulating the proliferation of primitive progenitors downstream of LT-HSCs.

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