Heterogeneous Nuclear Ribonucleoprotein L is required for the survival and functional integrity of murine hematopoietic stem cells.
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.
Institut de recherches cliniques de Montréal (IRCM) 110 Avenue des Pins, Montréal, QC H2W 1R7, Canada.|Département de microbiologie, infectiologie et immunologie, Université de Montréal, C.P. 6128, succ. Centre-ville, Montréal, H3C 3J7, Canada.
Marie-Claude
MC
Gaudreau
Institut de recherches cliniques de Montréal (IRCM) 110 Avenue des Pins, Montréal, QC H2W 1R7, Canada.|Département de microbiologie, infectiologie et immunologie, Université de Montréal, C.P. 6128, succ. Centre-ville, Montréal, H3C 3J7, Canada.
Damien
D
Grapton
Institut de recherches cliniques de Montréal (IRCM) 110 Avenue des Pins, Montréal, QC H2W 1R7, Canada.|Department of Experimental Medicine, McGill University, 1110 Pins Avenue West Room 101, Montréal, Quebec, H3A 1A3, Canada.
Anne
A
Helness
Institut de recherches cliniques de Montréal (IRCM) 110 Avenue des Pins, Montréal, QC H2W 1R7, Canada.|Département de microbiologie, infectiologie et immunologie, Université de Montréal, C.P. 6128, succ. Centre-ville, Montréal, H3C 3J7, Canada.
Charles
C
Vadnais
Institut de recherches cliniques de Montréal (IRCM) 110 Avenue des Pins, Montréal, QC H2W 1R7, Canada.|Département de microbiologie, infectiologie et immunologie, Université de Montréal, C.P. 6128, succ. Centre-ville, Montréal, H3C 3J7, Canada.
Jennifer
J
Fraszczak
Institut de recherches cliniques de Montréal (IRCM) 110 Avenue des Pins, Montréal, QC H2W 1R7, Canada.
Peiman
P
Shooshtarizadeh
Institut de recherche en immunologie et cancerologie (IRIC), Université de Montréal, 2950 Chemin de Polytechnique, Marcelle-Coutu Pavilion, Montréal, Quebec, H3T 1J4, Canada.
Brian
B
Wilhelm
Institut de recherches cliniques de Montréal (IRCM) 110 Avenue des Pins, Montréal, QC H2W 1R7, Canada.|Département de médecine, Faculté de médecine, Université de Montréal, Montréal, Canada.
François
F
Robert
Institut für Chemie und Biochemie, Freie Universität Berlin, Berlin, Germany.
Florian
F
Heyd
Institut de recherches cliniques de Montréal (IRCM) 110 Avenue des Pins, Montréal, QC H2W 1R7, Canada.|Département de microbiologie, infectiologie et immunologie, Université de Montréal, C.P. 6128, succ. Centre-ville, Montréal, H3C 3J7, Canada.
Tarik
T
Möröy
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D034664:Heterogeneous-Nuclear Ribonucleoprotein L / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D034664:Heterogeneous-Nuclear Ribonucleoprotein L; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505640:Tnfrsf10b protein, mouse; D016159:Tumor Suppressor Protein p53