Defective erythropoiesis in a mouse model of reduced Fbxo7 expression due to decreased p27 expression

Abstract

During the final stages of erythropoiesis, lineage-restricted progenitors mature over three to five cell divisions, culminating with withdrawal from the cell cycle and the loss of most organelles, including mitochondria and nuclei. Recent genome-wide association studies in human populations have associated several SNPs near or within FBXO7 with erythrocyte phenotypes. Fbxo7 encodes a multi-functional F-box protein known to bind p27 and participate in selective mitophagy. One SNP causes an amino acid substitution (Met115Ile) and is associated with smaller erythrocytes. We find that the less common IIe115 allele of Fbxo7 binds less efficiently to p27, and cells expressing this allele proliferate faster than cells expressing Met115. We show that an erythroleukaemic cell line with reduced Fbxo7 expression fails to stabilize p27 levels, exit the cell cycle, and produce haemoglobin. In addition, mice deficient in Fbxo7 expression are anaemic due to a reduction in erythrocyte numbers, and this is associated with lower p27 levels, increased numbers of late-stage erythroblasts with greater than 2N DNA content, and delayed mitophagy during terminal differentiation. Collectively, these data support an important physiological, cell cycle regulatory role for Fbxo7 during erythropoiesis. © 2015 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

F-box protein interactions with the hallmark pathways in cancer

“…This is because cell cycle arrest and differentiation are tightly linked, and it is interesting to note that prevention of one can lead to defects in the other. For example, during erythropoiesis in mice lacking Fbxo7 or overexpressing cyclin E, erythroblasts undergo more cell divisions yet fewer mature cells are produced, causing anaemia and other dysplastic phenotypes (63,64). Fbxo7, by virtue of its stabilisation of p27, can also slow B cell proliferation, and B cells lacking Fbxo7 have a faster cell cycle and show a concomitant reversal in differentiation markers, suggesting a linked mechanism whereby slowing the cell cycle aids differentiation (34).…”

Loss of FBXO7 results in a Parkinson's‐like dopaminergic degeneration via an RPL23–MDM2–TP53 pathway

“…To determine functional roles in vivo , we created Fbxo7 null mice, first by crossing Fbxo7 LacZ mice with ActB:FLPe animals , to generate a ‘floxed’ ( Fbxo7 fl ) allele, with LoxP sites flanking either side of exon 4 (Figure A), and subsequent breeding to Zp3 Cre mice , for germline excision ( Fbxo7 − ). Fbxo7 −/+ offspring were backcrossed with WT C57/BL6J mice and bred to homozygosity.…”

“…To generate a mouse in which Fbxo7 was lost specifically in dopaminergic neurons, Fbxo7 fl mice were bred with Dat Cre ROSA26 ‐stop‐ YFP animals, which express Cre from the dopamine transporter ( Dat ) promoter . Since our previous studies detected no phenotypes in mice heterozygous for Fbxo7 , we analysed Dat Cre Fbxo7 −/fl animals, which were systemically heterozygous for Fbxo7 expression, in addition to the loss of Fbxo7 expression in dopaminergic cells. Dat +/+ Fbxo7 −/+ and Dat Cre Fbxo7 −/+ mice were used as controls.…”

A conserved requirement forFbxo7during male germ cell cytoplasmic remodelling

“…In the course of our investigations into the physiological functions of mammalian Fbxo7, we generated mice that are either heterozygous or homozygous for an allele of Fbxo7 containing a LacZ insertion between exons 3 and 4 of Fbxo7 Randle et al, 2015). This insertion severely disrupts expression of all Fbxo7 isoforms but does not completely abolish it (Randle et al, 2015), and thus the phenotype(s) of the hetero-and homozygous animals can respectively be ascribed to moderate or severe under-expression of Fbxo7. In maintaining the colony of LacZ-transgenic animals, we observed that homozygous Fbxo7 LacZ/LacZ males never sired any offspring, while heterozygous males and all genotypes of female were able to produce litters.…”

“…interactions (Kuiken et al, 2012), and in cell cycle regulation via Cdk6 activation and p27 stabilisation Randle et al, 2015;Meziane et al, 2011;Laman, 2006).…”