title: Haploinsufficiency of senescence evasion factor causes defects of hematopoietic stem cells functions.
abstract: The quality of hematopoietic stem cells (HSCs) is essentially defined by two characteristics, i.e., multilineage differentiation and self-renewal capacity. Thus, it is of high priority to clarify mechanisms that regulate these functions and to understand them at the molecular level. In the present study, we investigated the role of senescence evasion factor (synonymously hPrp19,hPSO4,hNMP200: SNEV), a multifunctional protein involved in pre-mRNA splicing, regulation of replicative life span, and DNA repair. Here we report that murine SNEV mRNA expression is high in lineage-depleted (Lin(-)) precursor cells of the bone marrow immediately after isolation as compared to fully differentiated peripheral blood lymphocytes (PBLs). Furthermore, the progenitor cell subset with highest colony-forming ability and self-renewal capacity (Lin(-), Sca-1(+)) showed also the highest SNEV expression. To test if the observed differences in SNEV mRNA levels cause stem cell defects, Lin(-) cells derived from heterozygous SNEV knockout mice were tested for primary as well as secondary colony-forming potential as a measure of self-renewal capacity. Interestingly, both, primary and secondary colonies were significantly less formed from SNEV(+/-) cells, a defect that was rescued by ectopic SNEV expression. Similarly, bone marrow cells derived from the short-lived Senescence-Accelerated-Mouse-Prone (SAMP8) model showed similar differences in comparison to the aging-resistant (SAMR1) control strain. These data suggest that the expression of SNEV is closely associated with the growth of murine HSCs and determines the proliferative and repopulating capacity of phenotypically defined HSC subsets.
authors.affiliation: Institute of Pathophysiology and Immunology, Center of Molecular Medicine, Medical University of Graz, 8010 Graz, Austria. elisabeth.schraml@meduni-graz.at
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schraml
authors.forename: Regina
authors.initials: R
authors.lastname: Voglauer
authors.forename: Klaus
authors.initials: K
authors.lastname: Fortschegger
authors.forename: Maria
authors.initials: M
authors.lastname: Sibilia
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Stelzer
authors.forename: Johannes
authors.initials: J
authors.lastname: Grillari
authors.forename: Konrad
authors.initials: K
authors.lastname: Schauenstein
mesh_terms: D022981:Allelic Imbalance / Q000502:physiology*; D000818:Animals; D001773:Blood Cells / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D000072260:RNA Splicing Factors
chemical_list: D034521:Nuclear Matrix-Associated Proteins; C518638:Prpf19 protein, mouse; D000072260:RNA Splicing Factors