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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.

ORGANISM(S): Mus musculus

PROVIDER: GSE29432 | GEO | 2011/05/21

SECONDARY ACCESSION(S): PRJNA141505

REPOSITORIES: GEO

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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. 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.

2011-05-21 | E-GEOD-29432 | biostudies-arrayexpress

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LIGHT/LTβR signaling regulates self-renewal and differentiation of hematopoietic and leukemia stem cells

Project description:Purpose: The goal of this study is to compare NGS-derived transcriptome profiling (RNA-seq) of Ltbr-deficient and -proficient LT/ST-HSCs isolated from chimeric mice. Methods: Transcriptomic profiles of Ltbr-/- and Ly5.1 LT/ST-HSCs isolated from chimeric mice 6 weeks after reconstitution were assessed in triplicate by deep sequencing, using Illumina NextSeq 500. qRT–PCR validation was performed using TaqMan and SYBR Green assays. Results: We mapped about 60 million sequence reads per sample to the mouse genome (GRCm38 - mm10) and identified expressed transcripts in Ltbr-/- and Ly5.1 LT/ST-HSCs isolated from chimeric mice. RNA-seq. data confirmed stable expression of known housekeeping genes. Differentially expressed genes between the Ltbr-/- and Ly5.1 LT/ST-HSCs were identified with a fold change ≥1.5 and FDR p-value <0.05. Conclusions: Our study represents the first detailed transcriptome analysis of Ltbr-deficient and -proficient LT/ST-HSCs, with biologic replicates, generated by RNA-seq. technology. Our results show that Ltbr signaling regulates HSC proliferation and differentiation. Evaluation of mRNA content in Ltbr-/- LT/ST-HSCs revealed that Ltbr-deficiency enhances HSC proliferation, differentiation, cell cycle and reduces the activity of canonical NFkB signaling.

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