The<i>chianti</i>zebrafish mutant provides a model for erythroid-specific disruption of<i>transferrin receptor 1</i>

Wingert, Rebecca A.; Brownlie, Alison; Galloway, Jenna L.; Dooley, Kimberly; Fraenkel, Paula G.; Axe, Jennifer L.; Davidson, Alan J.; Barut, Bruce A.; Noriega, Laura; Sheng, Xiaoming; Zhou, Yi; Zon, Leonard I.

doi:10.1242/dev.01540

Cited by 65 publications

(62 citation statements)

References 66 publications

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“…PCR products were purified and sequenced directly. For characterization of gene expression, the following zebrafish anemia alleles were used: cia Tu25f , 18 cdy Te216,17 and gav IT029 .…”

Section: Methodsmentioning

confidence: 99%

“…Large-scale genetic screens for embryonic hypochromic anemia have identified recessive mutations in genes affecting iron acquisition and use including DMT1, 17 transferrin receptor 1a (TfR1a), 18 and ferroportin1 (fpn1). 19 Zebrafish embryos at 48 to 72 hours postfertilization (hpf), provide an excellent in vivo model for the study of hepcidin gene expression.…”

Section: Introductionmentioning

confidence: 99%

“…Morpholino sequences for TfR1a, TfR1b, and GATA1 were as described. 18,26 For each transferrin-a morpholino (MO), a mismatch control morpholino was synthesized with identical sequence, except for 5 nucleotide substitutions. Morpholinos that did not produce an anemia phenotype were tagged with 3Ј-fluorescein to indicate adequacy of injection.…”

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confidence: 99%

“…TfR1a cRNA was prepared as described. 18 The cRNA was injected at a concentration of 1600 ng/microliter, with or without Trf-MO2 (0.0625 mM). …”

mentioning

confidence: 99%

“…These findings complement studies in the zebrafish mutant chianti, which demonstrated that the erythroid transferrin receptor 1 (TfR1a) is required for hemoglobin production. 18 Gavi serves as a zebrafish model for congenital atransferrinemia, a rare condition in humans resulting in severe hypochromic anemia and premature death, 38,39 in the absence of intermittent plasma infusions, which partially restore serum transferrin levels. 40 Both alleles of gav (gav IT029 and gav HE067 ) are due to mutations that cause aberrant splicing of the transferrin-a message.…”

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confidence: 99%

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Transferrin-a modulates hepcidin expression in zebrafish embryos

Fraenkel

Gibert

Holzheimer

et al. 2009

Blood

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The iron regulatory hormone hepcidin is transcriptionally up-regulated in response to iron loading, but the mechanisms by which iron levels are sensed are not well understood. Large-scale genetic screens in the zebrafish have resulted in the identification of hypochromic anemia mutants with a range of mutations affecting conserved pathways in iron metabolism and heme synthesis. We hypothesized that transferrin plays a critical role both in iron transport and in regulating hepcidin expression in zebrafish embryos. Here we report the identification and characterization of the zebrafish hypochromic anemia mutant, gavi, which exhibits transferrin deficiency due to mutations in transferrin-a. Morpholino knockdown of transferrin-a in wild-type embryos reproduced the anemia phenotype and decreased somite and terminal gut iron staining, while coinjection of transferrin-a cRNA partially restored these defects. Embryos with transferrin-a or transferrin receptor 2 (TfR2) deficiency exhibited low levels of hepcidin expression, however anemia, in the absence of a defect in the transferrin pathway, failed to impair hepcidin expression. These data indicate that transferrin-a transports iron and that hepcidin expression is regulated by a transferrin-a-dependent pathway in the zebrafish embryo. IntroductionTransferrin, a serum protein with 2 iron binding sites, is the major carrier of ferric iron in human plasma and is required to deliver iron to developing erythroid and other cells. Iron-bound holotransferrin binds transferrin receptor 1 (TfR1) on the surface of the cell, resulting in endocytosis of an endosome containing both transferrin and TfR1 (reviewed in Aisen 1 ). After acidification of the endosome, ferrous iron exits the endosome via the divalent metal transporter (DMT1). 2,3 Transferrin receptor 2 (TfR2), a homolog of TfR1, with restricted expression to hepatocytes and erythroid cells, 4 binds transferrin at lower affinity than TfR1 5,6 and is involved in the regulation of iron homeostasis.As humans have no active means of iron excretion, maintaining iron homeostasis requires adjustment of iron absorption to reflect the body's iron stores. Hepcidin is a peptide hormone, primarily expressed in the liver, 7 which modulates iron absorption and iron delivery to erythrocytes by binding the iron transporter ferroportin (fpn), resulting in internalization and degradation of fpn. 8 In mammalian models, hepcidin is transcriptionally up-regulated in response to inflammation 9,10 or iron overload 11 and down-regulated in response to anemia, iron deficiency, or hypoxia. 9 Although mutations in HFE, 12 transferrin receptor 2 (TFR2), 13 hepcidin (HAMP), 14 or hemojuvelin (HJV or HFE2) 15 have each been associated with hemochromatosis and impaired hepcidin expression, 16 the mechanisms by which iron overload is sensed and hepcidin is regulated are not completely understood.The zebrafish, Danio rerio, provides an excellent system for the identification and analysis of genes involved in iron metabolism and erythroid development. La...

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“…PCR products were purified and sequenced directly. For characterization of gene expression, the following zebrafish anemia alleles were used: cia Tu25f , 18 cdy Te216,17 and gav IT029 .…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

“…TfR1a cRNA was prepared as described. 18 The cRNA was injected at a concentration of 1600 ng/microliter, with or without Trf-MO2 (0.0625 mM). …”

mentioning

confidence: 99%

mentioning

confidence: 99%

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Transferrin-a modulates hepcidin expression in zebrafish embryos

Fraenkel

Gibert

Holzheimer

et al. 2009

Blood

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Iron and Heme Transport and Trafficking

Yien

Paw

2004

Encyclopedia of Inorganic and Bioinorganic Chemistry

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Genetic defects in iron acquisition and export, and heme metabolism can result in pathologies including congenital anemia or porphyria. While the enzymes that govern heme synthesis have been elucidated and characterized, the proteins and genes that govern the transport of iron, heme, and heme intermediates are poorly studied. Knowledge of these transport mechanisms will shed light on important regulatory steps that govern heme and iron metabolism. This article focuses on summarizing current studies on heme, heme intermediates and iron transport, and attempts to identify gaps in our knowledge of these transport pathways. Additionally, we will highlight the contribution of model organisms to the understanding of heme/iron metabolism.

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Egfl7 knockdown causes defects in the extension and junctional arrangements of endothelial cells during zebrafish vasculogenesis

Mazière

Parker²,

Dijk

et al. 2008

Developmental Dynamics

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The endothelial cell (EC) -specific secreted protein EGFL7 is important for tubulogenesis in newly forming blood vessels. We studied its role in vascular tube formation by a quantitative ultrastructural analysis of Egfl7-knockdown zebrafish embryos. At 24 hours postfertilization, the endothelia of dorsal aorta (DA) and posterior cardinal vein (PCV) were correctly anchored to the hypochord and endoderm, respectively, but failed to expand into the vascular area. This resulted in vessels with reduced or split lumen and open sheets of ECs. Concomitantly, the organization of hematopoietic cells-identified by the presence of previously undescribed membrane tubules-between DA and PCV, and within the vessels, was severely disturbed. Strikingly, ectopic cell junctions occurred across the obstructed vessel lumen, on the luminal EC surfaces, which in control conditions never display junctions of any kind. These data suggest that Egfl7 provides ECs with a cue for their extension into the vascular area and in establishing EC cell polarity. Developmental Dynamics 237:580 -591, 2008.

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Thechiantizebrafish mutant provides a model for erythroid-specific disruption oftransferrin receptor 1

Cited by 65 publications

References 66 publications

Transferrin-a modulates hepcidin expression in zebrafish embryos

Transferrin-a modulates hepcidin expression in zebrafish embryos

Iron and Heme Transport and Trafficking

Egfl7 knockdown causes defects in the extension and junctional arrangements of endothelial cells during zebrafish vasculogenesis

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