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The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation
Deborah Chiabrando, … , Paolo Pinton, Emanuela Tolosano
Deborah Chiabrando, … , Paolo Pinton, Emanuela Tolosano
Published December 3, 2012; First published November 26, 2012
Citation Information: J Clin Invest. 2012;122(12):4569-4579. https://doi.org/10.1172/JCI62422.
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Category: Research Article

The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation

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Abstract

Feline leukemia virus subgroup C receptor 1 (FLVCR1) is a cell membrane heme exporter that maintains the balance between heme levels and globin synthesis in erythroid precursors. It was previously shown that Flvcr1-null mice died in utero due to a failure of erythropoiesis. Here, we identify Flvcr1b, a mitochondrial Flvcr1 isoform that promotes heme efflux into the cytoplasm. Flvcr1b overexpression promoted heme synthesis and in vitro erythroid differentiation, whereas silencing of Flvcr1b caused mitochondrial heme accumulation and termination of erythroid differentiation. Furthermore, mice lacking the plasma membrane isoform (Flvcr1a) but expressing Flvcr1b had normal erythropoiesis, but exhibited hemorrhages, edema, and skeletal abnormalities. Thus, FLVCR1b regulates erythropoiesis by controlling mitochondrial heme efflux, whereas FLVCR1a expression is required to prevent hemorrhages and edema. The aberrant expression of Flvcr1 isoforms may play a role in the pathogenesis of disorders characterized by an imbalance between heme and globin synthesis.

Authors

Deborah Chiabrando, Samuele Marro, Sonia Mercurio, Carlotta Giorgi, Sara Petrillo, Francesca Vinchi, Veronica Fiorito, Sharmila Fagoonee, Annalisa Camporeale, Emilia Turco, Giorgio R. Merlo, Lorenzo Silengo, Fiorella Altruda, Paolo Pinton, Emanuela Tolosano

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Figure 4

FLVCR1b controls erythroid differentiation in vivo.

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FLVCR1b controls erythroid differentiation in vivo.
(A) Schematic repres...
(A) Schematic representation of the targeting strategy. The start codon in the first exon of the Flvcr1 gene was disrupted by the insertion of the neomycin resistance cassette by homologous recombination in mouse ES cells. (B) Southern blot analysis on genomic DNA extracted from a recombinant and a wild-type clone, digested with EcoRV, and hybridized with the probe shown in A. (C) RT-PCR analysis of Flvcr1 isoforms levels in wild-type and Flvcr1a–/– embryos at E13.5. Two different pairs of primers were used in lanes 1 and 2. (D) qRT-PCR analysis of Flvcr1b mRNA on E13.5 wild-type and Flvcr1a–/– embryos. n = 6. t test. ***P < 0.001. (E) Erythroid differentiation is completely normal in Flvcr1a–/– fetal liver. Representative flow cytometric analyses of E14.5 liver cells from wild-type and Flvcr1a–/– embryos immunostained with antibodies to CD71 and Ter119. Regions R2–R5 corresponding to different maturational stages are indicated. The percentage of cells in each population is reported (F). n = 6. (G) Representative flow cytometric analyses of bone marrow cells, isolated from mice transplanted with wild-type or Flvcr1a–/– fetal liver cells, immunostained with antibodies to CD71 and Ter119. Regions R2–R5 corresponding to different maturational stages are indicated. The percentage of cells in each population is reported (H). n = 6. Values represent mean ± SEM.
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