Erythroid overproduction of erythroferrone causes iron overload and developmental abnormalities in mice

Coffey, Richard; Jung, Grace; Pereira, Renata C.; Nemeth, Elizabeta; Ganz, Tomas

doi:10.1101/2021.01.09.426054

Cited by 5 publications

(15 citation statements)

References 74 publications

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“…These findings may reflect the lesser degree of ERFE elevation in PV compared with diseases of ineffective erythropoiesis such as thalassaemia 60 . Elevations of ERFE in our model of PV were comparable to elevations detected in experimental ‘low’ level ERFE-overexpressing mice, where modest elevations in serum and liver iron were detected, but expression of hepcidin was unchanged 61 .…”

Section: Discussionsupporting

confidence: 77%

Iron homeostasis governs erythroid phenotype in Polycythemia Vera

Bennett

Jackson

Pettikiriarachchi

et al. 2022

Preprint

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Polycythemia Vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients’ hematocrit and hemoglobin concentration, placing them at risk of life-threatening thrombotic events. Our GWAS of 440 PV cases and 403,351 controls utilising UK Biobank data found that SNPs in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed over-representation of homozygous HFE mutations in PV patients. HFE influences expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of PV mouse models, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Further, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signalling via GP130 coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.

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Section: Discussionsupporting

confidence: 77%

Iron homeostasis governs erythroid phenotype in Polycythemia Vera

Bennett

Jackson

Pettikiriarachchi

et al. 2022

Preprint

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“…The measurements of serum iron concentration and transferrin saturation (TSAT) were precluded at ED17.5 and PD7 due to a limited volume of samples. The activation of Bmp/Smad pathway, responsible for iron‐induced hepcidin production, was partly blunted in both heterozygous and homozygous mtHEPOR newborns, as documented by diminished expression of two Bmp/Smad target genes, 7 Smad7 and Id1 (Figure S2A). Thus, available iron status data, together with reduced RBC indices (MCH and MCHC), as a whole support the conclusion about transient iron deficiency.…”

Section: Resultsmentioning

confidence: 99%

“…5,6 The transgenic mice with graded erythroid overexpression of Erfe develop dose-dependent iron overload and relative hepcidin deficiency. 7 The co-regulation of erythropoiesis and iron metabolism as exemplified by ERFE is less clear in congenital diseases characterized by chronically elevated effective erythropoiesis. 8 Decreased circulating hepcidin concentrations and iron deficiency were reported among individuals with Chuvash polycythemia, 9 the congenital erythrocytosis characterized by augmented hypoxia-induced transcription factors (HIFs) due to a hypomorphic mutation of negative HIFs regulator von Hippel Lindau gene (VHL R200W ).…”

mentioning

confidence: 99%

Developmental changes in iron metabolism and erythropoiesis in mice with human gain‐of‐function erythropoietin receptor

et al. 2022

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Iron availability for erythropoiesis is controlled by the iron‐regulatory hormone hepcidin. Increased erythropoiesis negatively regulates hepcidin synthesis by erythroferrone (ERFE), a hormone produced by erythroid precursors in response to erythropoietin (EPO). The mechanisms coordinating erythropoietic activity with iron homeostasis in erythrocytosis with low EPO are not well defined as exemplified by dominantly inherited (heterozygous) gain‐of‐function mutation of human EPO receptor (mtHEPOR) with low EPO characterized by postnatal erythrocytosis. We previously created a mouse model of this mtHEPOR that develops fetal erythrocytosis with a transient perinatal amelioration of erythrocytosis and its reappearance at 3–6 weeks of age. Prenatally and perinatally, mtHEPOR heterozygous and homozygous mice (differing in erythrocytosis severity) had increased Erfe transcripts, reduced hepcidin, and iron deficiency. Epo was transiently normal in the prenatal life; then decreased at postnatal day 7, and remained reduced in adulthood. Postnatally, hepcidin increased in mtHEPOR heterozygotes and homozygotes, accompanied by low Erfe induction and iron accumulation. With aging, the old, especially mtHEPOR homozygotes had a decline of erythropoiesis, myeloid expansion, and local bone marrow inflammatory stress. In addition, mtHEPOR erythrocytes had a reduced lifespan. This, together with reduced iron demand for erythropoiesis, due to its age‐related attenuation, likely contributes to increased iron deposition in the aged mtHEPOR mice. In conclusion, the erythroid drive‐mediated inhibition of hepcidin production in mtHEPOR mice in the prenatal/perinatal period is postnatally abrogated by increasing iron stores promoting hepcidin synthesis. The differences observed in studied characteristics between mtHEPOR heterozygotes and homozygotes suggest dose‐dependent alterations of downstream EPOR stimulation.

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“…Liver hepcidin expression in iron-replete dams was similar between all ERFE genotypes (Figure 2G,H) but hepcidin expression relative to liver iron load was significantly lower in TG dams (Figure S2B), consistent with previous data. 19 In the irondeficient diet group, where TG iron overload was precluded, Hamp expression was significantly decreased in ERFE TG dams compared to WT (ÀΔCt À1.2 to 1.2, p = 0.025 t-test) (Figure 2G). Serum hepcidin was likewise decreased (2.8 ± 3.2 vs. 4.8 ± 4.1 ng/mL), although the difference did not reach statistical significance due to the overall low concentrations (Figure 2H).…”

Section: The Effects Of Altered Erfe Levels During Pregnancy On Mater...mentioning

confidence: 95%

“…Experiments were conducted in accordance with guidelines by the Animal Research Committee and were approved by the University of California, Los Angeles (UCLA). ERFE transgenic (Erfe TG) mice were generated in our lab 19 Erfe KO mice (Fam132b À/À ) genotyping was performed via PCR using ear punch DNA isolated with the Gentra Puregene Core Kit A (Qiagen). The PCR reaction was run using GoTaq G2 Green Master Mix (Promega).…”

Section: Micementioning

confidence: 99%

Erythroferrone contributes to iron mobilization for embryo erythropoiesis in iron‐deficient mouse pregnancies

Sangkhae

Coffey

et al. 2022

American J Hematol

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Erythroferrone (ERFE) is an erythroblast‐secreted regulator of iron metabolism. The production of ERFE increases during stress erythropoiesis, leading to decreased hepcidin expression and mobilization of iron. Pregnancy requires a substantial increase in iron availability to sustain maternal erythropoietic expansion and fetal development and is commonly affected by iron deficiency. To define the role of ERFE during iron‐replete or iron‐deficient pregnancy, we utilized mouse models expressing a range of ERFE levels: transgenic (TG) mice overexpressing ERFE, wild‐type (WT), and ERFE knockout (KO) mice. We altered maternal iron status using diets with low or standard iron content and performed the analysis at E18.5. Iron deficiency increased maternal ERFE in WT pregnancy. Comparing different maternal genotypes, ERFE TG dams had lower hepcidin relative to their liver iron load but similar hematological parameters to WT dams on either diet. In ERFE KO dams, most hematologic and iron parameters were comparable to WT, but mean corpuscular volume (MCV) was decreased under both iron conditions. Similar to dams, TG embryos had lower hepcidin on both diets, but their hematologic parameters did not differ from those of WT embryos. ERFE KO embryos had lower MCV than WT embryos on both diets. The effect was exacerbated under iron‐deficient conditions where ERFE KO embryos had higher hepcidin, lower Hb and Hct, and lower brain iron concentration compared to WT embryos, indicative of iron restriction. Thus, under iron‐deficient conditions, maternal and embryo ERFE facilitate iron mobilization for embryonic erythropoiesis.

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Erythroid overproduction of erythroferrone causes iron overload and developmental abnormalities in mice

Cited by 5 publications

References 74 publications

Iron homeostasis governs erythroid phenotype in Polycythemia Vera

Iron homeostasis governs erythroid phenotype in Polycythemia Vera

Developmental changes in iron metabolism and erythropoiesis in mice with human gain‐of‐function erythropoietin receptor

Erythroferrone contributes to iron mobilization for embryo erythropoiesis in iron‐deficient mouse pregnancies

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