Abstract
The proliferation and survival of hematopoietic stem cells (HSCs) has to be strictly coordinated to ensure the timely production of all blood cells. Here we report that the splice factor and RNA binding protein hnRNP L (heterogeneous nuclear ribonucleoprotein L) is required for hematopoiesis, since its genetic ablation in mice reduces almost all blood cell lineages and causes premature death of the animals. In agreement with this, we observed that hnRNP L deficient HSCs lack both the ability to self-renew and foster hematopoietic differentiation in transplanted hosts. They also display mitochondrial dysfunction, elevated levels of γH2AX, are Annexin V positive and incorporate propidium iodide indicating that they undergo cell death. Lin-c-Kit+ fetal liver cells from hnRNP L deficient mice show high p53 protein levels and up-regulation of p53 target genes. In addition, cells lacking hnRNP L up-regulated the expression of the death receptors TrailR2 and CD95/Fas and show Caspase-3, Caspase-8 and Parp cleavage. Treatment with the pan-caspase inhibitor Z-VAD-fmk, but not the deletion of p53, restored cell survival in hnRNP L deficient cells. Our data suggest that hnRNP L is critical for the survival and functional integrity of HSCs by restricting the activation of caspase-dependent death receptor pathways.
Highlights
In mice, hematopoiesis originates from hematopoietic stem cells (HSC) that migrate from the aorta-gonad-mesonephros region (AGM) towards the fetal liver (FL) at embryonal stage 10.5 day post-coitus and later on, takes place in the bone marrow (BM) of adult mice[1,2]
We present evidence that Heterogeneous nuclear ribonucleoprotein L (hnRNP L) is essential for the survival and functional integrity of HSCs since ablation of this factor is incompatible with proper hematopoietic differentiation and causes premature and accelerated death in hnRNP L deficient animals
HnRNP Lfl/fl mice were crossed with animals carrying the polyinosinic-polycytidylic acid (pIpC) inducible Mx-Cre transgene, but an acute ablation of hnRNP L by pIpC injection caused MxCre+hnRNP Lfl/fl mice to die quickly (Fig. 1b)
Summary
Hematopoiesis originates from hematopoietic stem cells (HSC) that migrate from the aorta-gonad-mesonephros region (AGM) towards the fetal liver (FL) at embryonal stage 10.5 day post-coitus and later on, takes place in the bone marrow (BM) of adult mice[1,2]. In both FL and BM, HSCs possess a unique self-renewal capacity and the potential to generate all mature blood and immune cells of an organism throughout its lifetime[3,4,5]. We report that hnRNP L deficient HSCs show increased mitochondrial stress and initiate both p53- and caspase-dependent cell death pathways
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