Haploinsufficiency of SNEV 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.

Decline of Bone Marrow–Derived Hematopoietic Progenitor Cell Quality During Aging in the Rat

“…In recent years, increasing evidence suggests that hematopoietic stem and progenitor cells (HSCs) are affected by the aging process similarly to all other somatic cells (de Haan, Nijhof, & Van Zant, 1997;Rossi et al, 2005). Additionally, based on data derived from myeloid secondary colony formation assays, we could recently show that the proliferative capacity of murine HSCs is closely associated with the expression of the senescence evasion factor (SNEV) (Schraml et al, 2008).…”

The Splicing Factor SRSF1 as a Marker for Endothelial Senescence

“…In addition to being involved in spliceosome assembly and stabilization, SNEV regulates proteasome function due to its U3-ligase activity, and is involved in DNA repair (Grillari et al, 2010). Furthermore, the haploinsufficiency of SNEV has been demonstrated using a heterozygous mouse model, which showed that the proliferative and repopulating capacity of hematopoietic stem cells from these mice was clearly compromised (Schraml et al, 2008). …”

Blom7α Is a Novel Heterogeneous Nuclear Ribonucleoprotein K Homology Domain Protein Involved in Pre-mRNA Splicing That Interacts with SNEVPrp19-Pso4

“…To merge the different names of SNEV that derive from the yeast homologue that were synonymously termed Pso4 as well as Prp19, we suggest here to use SNEV Prp19-Pso4 . Knock-out of SNEV Prp19-Pso4 in mice is early embryonic lethal, whereas embryonic fibroblasts from heterozygous SNEV Prp19-Pso4+/− mice show reduced replicative life span (23) and hematopoietic progenitor defects in proliferation and self-renewal (24). This effect might be due to its additional function as a DNA repair factor (25, 26), especially in interstrand cross-link repair, where it interacts with WRN, the protein mutated in the premature progeroid Werner syndrome (27).…”