Home LiteratureArticle Details
PMID: 19154717 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Scara5 is a ferritin receptor mediating non-transferrin iron delivery.

Developmental cell ·Vol. 16 ·No. 1 ·2009-01-00 ·Pages 35-46

Li JY, Paragas N, Ned RM, Qiu A, Viltard M, Leete T, Drexler IR, Chen X, Sanna-Cherchi S, Mohammed F, Williams D, Lin CS, Schmidt-Ott KM, Andrews NC, Barasch J

Abstract

Developing organs require iron for a myriad of functions, but embryos deleted of the major adult transport proteins, transferrin or its receptor transferrin receptor1 (TfR1(-/-)), still initiate organogenesis, suggesting that non-transferrin pathways are important. To examine these pathways, we developed chimeras composed of fluorescence-tagged TfR1(-/-) cells and untagged wild-type cells. In the kidney, TfR1(-/-) cells populated capsule and stroma, mesenchyme and nephron, but were underrepresented in ureteric bud tips. Consistently, TfR1 provided transferrin to the ureteric bud, but not to the capsule or the stroma. Instead of transferrin, we found that the capsule internalized ferritin. Since the capsule expressed a novel receptor called Scara5, we tested its role in ferritin uptake and found that Scara5 bound serum ferritin and then stimulated its endocytosis from the cell surface with consequent iron delivery. These data implicate cell type-specific mechanisms of iron traffic in organogenesis, which alternatively utilize transferrin or non-transferrin iron delivery pathways.

MeSH Terms
Animals Biological Transport Cell Line Chimera/physiology Endocytosis/physiology Ferritins/metabolism Iron/metabolism Iron-Binding Proteins/genetics,metabolism Kidney/embryology,metabolism Mice Mice, Inbred C57BL Mice, Knockout Morphogenesis/physiology Receptors, Cell Surface/genetics,metabolism Receptors, Transferrin/genetics,metabolism Scavenger Receptors, Class A/genetics,metabolism Transferrin/metabolism
Chemicals
Iron-Binding Proteins Receptors, Cell Surface Receptors, Transferrin SCARA5 protein, mouse Scavenger Receptors, Class A Tfrc protein, mouse Transferrin ferritin receptor Ferritins Iron
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Li Jau Yi
Renal Division, College of Physicans & Surgeons, Columbia University, New York, NY 10032, USA.
Paragas Neal
Ned Renee M
Qiu Andong
Viltard Melanie
Leete Thomas
Drexler Ian R
Chen Xia
Sanna-Cherchi Simone
Mohammed Farah
Williams David
Lin Chyuan Sheng
Schmidt-Ott Kai M
Andrews Nancy C
Barasch Jonathan
References (83)
83 references, click to expand
  1. The relationship between maternal and infant iron status.
    Scand J Haematol. 1980 Aug;25(2):141-50 PMID: 7466303
  2. Crystal structure of the cysteine-rich domain of scavenger receptor MARCO reveals the presence of a basic and an acidic cluster that both contribute to ligand recognition.
    J Biol Chem. 2007 Jun 1;282(22):16654-66 PMID: 17405873
  3. Inhibition of proliferation and differentiation during early T cell development by anti-transferrin receptor antibody.
    Eur J Immunol. 1994 Nov;24(11):2896-902 PMID: 7957580
  4. Transferrin receptor is necessary for development of erythrocytes and the nervous system.
    Nat Genet. 1999 Apr;21(4):396-9 PMID: 10192390
  5. Cellular distribution of iron, transferrin, and ferritin in the hypotransferrinemic (Hp) mouse brain.
    J Comp Neurol. 1995 Apr 24;355(1):67-80 PMID: 7636015
  6. Beta-catenin is necessary to keep cells of ureteric bud/Wolffian duct epithelium in a precursor state.
    Dev Biol. 2008 Feb 1;314(1):112-26 PMID: 18177851
  7. Mechanisms of differential transferrin receptor expression in normal hematopoiesis.
    Eur J Biochem. 2000 Dec;267(23):6762-74 PMID: 11082186
  8. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver.
    J Clin Invest. 2005 May;115(5):1258-66 PMID: 15849611
  9. Transferrin as a fetal growth factor: acquisition of responsiveness related to embryonic induction.
    Proc Natl Acad Sci U S A. 1983 May;80(9):2651-5 PMID: 6405384
  10. Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis.
    Dev Genet. 1999;24(3-4):241-51 PMID: 10322632
  11. Function and regulation of transferrin and ferritin.
    Semin Hematol. 1998 Jan;35(1):35-54 PMID: 9460808
  12. Developmental changes in microheterogeneity of foetal plasma glycoproteins of mice.
    Biochem J. 1973 Mar;132(3):541-51 PMID: 4353382
  13. Studies on familial hypotransferrinemia: unique clinical course and molecular pathology.
    Am J Hum Genet. 1993 Jul;53(1):201-13 PMID: 8317485
  14. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells.
    Nat Genet. 2005 Nov;37(11):1264-9 PMID: 16227996
  15. Mechanism of ferritin iron uptake: activity of the H-chain and deletion mapping of the ferro-oxidase site. A study of iron uptake and ferro-oxidase activity of human liver, recombinant H-chain ferritins, and of two H-chain deletion mutants.
    J Biol Chem. 1988 Dec 5;263(34):18086-92 PMID: 3192527
  16. Relationship of a mouse Sertoli cell line (MSC-1) to normal Sertoli cells.
    Biol Reprod. 1994 Jul;51(1):116-24 PMID: 7918865
  17. Iron in cytosolic ferritin can be recycled through lysosomal degradation in human fibroblasts.
    Biochem J. 1998 Nov 15;336 ( Pt 1):201-5 PMID: 9806901
  18. Characterisation and trophic functions of murine embryonic macrophages based upon the use of a Csf1r-EGFP transgene reporter.
    Dev Biol. 2007 Aug 1;308(1):232-46 PMID: 17597598
  19. Novel regulators of kidney development from the tips of the ureteric bud.
    J Am Soc Nephrol. 2005 Jul;16(7):1993-2002 PMID: 15917337
  20. Iron content of rat serum ferritin.
    J Vet Med Sci. 2001 May;63(5):587-9 PMID: 11411511
  21. Oligodendrocyte progenitor cells internalize ferritin via clathrin-dependent receptor mediated endocytosis.
    J Neurosci Res. 2000 Jul 1;61(1):52-60 PMID: 10861799
  22. Ovotransferrin and ovotransferrin receptor expression during chondrogenesis and endochondral bone formation in developing chick embryo.
    J Cell Biol. 1994 Feb;124(4):579-88 PMID: 8106555
  23. The chianti zebrafish mutant provides a model for erythroid-specific disruption of transferrin receptor 1.
    Development. 2004 Dec;131(24):6225-35 PMID: 15563524
  24. Transferrin receptor 1.
    Int J Biochem Cell Biol. 2004 Nov;36(11):2137-43 PMID: 15313461
  25. Studies of the ultrastructure and permeability of the blood-brain barrier in the developing corpus callosum in postnatal rat brain using electron dense tracers.
    J Anat. 1994 Apr;184 ( Pt 2):227-37 PMID: 8014116
  26. Macrophages function as a ferritin iron source for cultured human erythroid precursors.
    J Cell Biochem. 2008 Mar 1;103(4):1211-8 PMID: 17902167
  27. Functional expression of the human transferrin receptor cDNA in Chinese hamster ovary cells deficient in endogenous transferrin receptor.
    J Cell Biol. 1987 Jul;105(1):207-14 PMID: 3611186
  28. Ferritin: a novel mechanism for delivery of iron to the brain and other organs.
    Am J Physiol Cell Physiol. 2007 Aug;293(2):C641-9 PMID: 17459943
  29. Regulation of intracellular iron metabolism in human erythroid precursors by internalized extracellular ferritin.
    Blood. 1999 Nov 1;94(9):3205-11 PMID: 10556209
  30. Characterization and distribution of ferritin binding sites in the adult mouse brain.
    J Neurochem. 1999 Feb;72(2):868-74 PMID: 9930764
  31. Relation of maternal and cord blood serum ferritin.
    Arch Dis Child. 1977 Oct;52(10):782-4 PMID: 931424
  32. Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2.
    Genes Dev. 1996 Jun 15;10(12):1467-78 PMID: 8666231
  33. Serum ferritin: does it differ from tissue ferritin?
    J Gastroenterol Hepatol. 1996 Nov;11(11):1033-6 PMID: 8985824
  34. Transferrin is required for early T-cell differentiation.
    Immunology. 2004 Aug;112(4):543-9 PMID: 15270724
  35. Fine structure of the mammalian renal capsule: the atypical smooth muscle cell and its functional meaning.
    Cell Tissue Res. 1978 Dec 29;195(3):381-94 PMID: 728976
  36. H ferritin knockout mice: a model of hyperferritinemia in the absence of iron overload.
    Blood. 2001 Aug 1;98(3):525-32 PMID: 11468145
  37. The role of macrophages in clearing programmed cell death in the developing kidney.
    Anat Embryol (Berl). 1996 Oct;194(4):341-8 PMID: 8896697
  38. New functions for an iron storage protein: the role of ferritin in immunity and autoimmunity.
    J Autoimmun. 2008 Feb-Mar;30(1-2):84-9 PMID: 18191543
  39. Ferritin uptake by human erythroid precursors is a regulated iron uptake pathway.
    Blood. 1996 Oct 15;88(8):3200-7 PMID: 8874221
  40. Secretion of ferritin by iron-laden macrophages and influence of lipoproteins.
    Free Radic Res. 2004 Oct;38(10):1133-42 PMID: 15512802
  41. The role of the L-chain in ferritin iron incorporation. Studies of homo and heteropolymers.
    J Mol Biol. 1994 May 20;238(5):649-54 PMID: 8182740
  42. Detection and isolation of a hepatic membrane receptor for ferritin.
    J Biol Chem. 1983 Apr 25;258(8):4672-5 PMID: 6300097
  43. A splicing defect in the mouse transferrin gene leads to congenital atransferrinemia.
    Blood. 1989 Jul;74(1):482-6 PMID: 2752125
  44. Charged collagen structure mediates the recognition of negatively charged macromolecules by macrophage scavenger receptors.
    J Biol Chem. 1993 Jan 25;268(3):2126-33 PMID: 8380589
  45. Distribution of ferritin receptors and coated pits on giant HeLa cells.
    EMBO J. 1983;2(4):599-603 PMID: 6138252
  46. Caco-2 intestinal epithelial cells absorb soybean ferritin by mu2 (AP2)-dependent endocytosis.
    J Nutr. 2008 Apr;138(4):659-66 PMID: 18356317
  47. Proteoglycans are required for maintenance of Wnt-11 expression in the ureter tips.
    Development. 1996 Nov;122(11):3627-37 PMID: 8951078
  48. Congenital atransferrinemia. A case report and review of the literature.
    Am J Clin Pathol. 1991 Aug;96(2):215-8 PMID: 1862777
  49. Apoptosis in metanephric development.
    J Cell Biol. 1992 Dec;119(5):1327-33 PMID: 1447305
  50. c-kit delineates a distinct domain of progenitors in the developing kidney.
    Dev Biol. 2006 Nov 1;299(1):238-49 PMID: 16942767
  51. Detection of intracellular iron by its regulatory effect.
    Am J Physiol Cell Physiol. 2004 Dec;287(6):C1547-59 PMID: 15282194
  52. Stromal progenitors are important for patterning epithelial and mesenchymal cell types in the embryonic kidney.
    Semin Cell Dev Biol. 2003 Aug;14(4):225-31 PMID: 14627121
  53. Bud formation precedes the appearance of differential cell proliferation during branching morphogenesis of mouse lung epithelium in vitro.
    Dev Dyn. 1998 Oct;213(2):228-35 PMID: 9786423
  54. Pattern and regulation of cell proliferation during murine ureteric bud development.
    J Anat. 2004 Apr;204(4):241-55 PMID: 15061751
  55. Fetal rat utilization of 55Fe absorbed by fetal intestine from swallowed amniotic fluid.
    Blood. 1974 Mar;43(3):429-36 PMID: 4811825
  56. Characterization of the ferritin receptors of human T lymphoid (MOLT-4) cells.
    J Lab Clin Med. 1992 Mar;119(3):273-9 PMID: 1311740
  57. Ferritin, iron homeostasis, and oxidative damage.
    Free Radic Biol Med. 2002 Aug 15;33(4):457-63 PMID: 12160928
  58. The cellular basis of kidney development.
    Annu Rev Cell Dev Biol. 2006;22:509-29 PMID: 16822174
  59. CSR, a scavenger receptor-like protein with a protective role against cellular damage causedby UV irradiation and oxidative stress.
    Hum Mol Genet. 1998 Jun;7(6):1039-46 PMID: 9580669
  60. The fate of intravenously injected tissue ferritin in pregnant guinea-pigs.
    Br J Haematol. 1989 May;72(1):100-5 PMID: 2736234
  61. Evidence of H- and L-chains have co-operative roles in the iron-uptake mechanism of human ferritin.
    Biochem J. 1992 Dec 1;288 ( Pt 2):591-6 PMID: 1463463
  62. The assessment of newborn iron stores at birth: a review of the literature and standards for ferritin concentrations.
    Neonatology. 2007;92(2):73-82 PMID: 17361090
  63. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus.
    BMC Dev Biol. 2001;1:4 PMID: 11299042
  64. TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis.
    J Exp Med. 2005 Oct 3;202(7):955-65 PMID: 16203866
  65. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption.
    Cell. 2006 Dec 1;127(5):917-28 PMID: 17129779
  66. Identification and characterization of murine SCARA5, a novel class A scavenger receptor that is expressed by populations of epithelial cells.
    J Biol Chem. 2006 Apr 28;281(17):11834-45 PMID: 16407294
  67. Regulated secretion of glycosylated human ferritin from hepatocytes.
    Blood. 2004 Mar 15;103(6):2369-76 PMID: 14615366
  68. Hemoglobin and serum ferritin levels in mothers and infants at birth.
    Eur J Pediatr. 1980 Aug;134(2):125-7 PMID: 7439198
  69. Cloning of mouse c-ros renal cDNA, its role in development and relationship to extracellular matrix glycoproteins.
    Kidney Int. 1995 Nov;48(5):1646-59 PMID: 8544427
  70. Expression and structural and functional properties of human ferritin L-chain from Escherichia coli.
    Biochemistry. 1989 Jun 13;28(12):5179-84 PMID: 2669970
  71. Serum ferritin in the diagnosis of anemia during pregnancy.
    Acta Obstet Gynecol Scand Suppl. 1980;95:57-63 PMID: 6935913
  72. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron.
    Nature. 2004 Dec 16;432(7019):917-21 PMID: 15531878
  73. Secretion of ferritin by rat hepatoma cells and its regulation by inflammatory cytokines and iron.
    Blood. 1997 Dec 15;90(12):4979-86 PMID: 9389717
  74. Localisation of proteins of iron metabolism in the human placenta and liver.
    Br J Haematol. 2006 Sep;134(5):532-43 PMID: 16856887
  75. Commitment of neutrophilic differentiation and proliferation of HL-60 cells coincides with expression of transferrin receptor. Effect of granulocyte colony stimulating factor on differentiation and proliferation.
    J Biol Chem. 1999 Sep 3;274(36):25471-80 PMID: 10464278
  76. Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinaemia and cataract.
    Nat Genet. 1995 Dec;11(4):444-6 PMID: 7493028
  77. Subcellular localization of ferritin and iron taken up by rat hepatocytes.
    Biochem J. 1989 Sep 1;262(2):685-8 PMID: 2803277
  78. Iron speciation in hypotransferrinaemic mouse serum.
    Biochem Soc Trans. 1991 Aug;19(3):317S PMID: 1783153
  79. The molecular defect in hypotransferrinemic mice.
    Blood. 2000 Aug 1;96(3):1113-8 PMID: 10910930
  80. Uptake of iron from N-terminal half-transferrin by isolated rat hepatocytes. Evidence of transferrin-receptor-independent iron uptake.
    Eur J Biochem. 1995 Aug 15;232(1):129-33 PMID: 7556141
  81. Transferrin receptor 1 is differentially required in lymphocyte development.
    Blood. 2003 Nov 15;102(10):3711-8 PMID: 12881306
  82. A correlation between epithelial proliferation rates, basement membrane component localization patterns, and morphogenetic potential in the embryonic mouse lung.
    Am J Respir Cell Mol Biol. 1998 Jul;19(1):71-82 PMID: 9651182
  83. Developmental changes in the expression of iron regulatory proteins and iron transport proteins in the perinatal rat brain.
    J Neurosci Res. 2002 Jun 15;68(6):761-75 PMID: 12111837
Article Info
Journal
Developmental cell
Abbr.
Dev Cell
ISSN
1878-1551
DOI
10.1016/j.devcel.2008.12.002
Published
2009-01-00
Pages
35-46
Language
English
Region
United States
NLM ID
101120028
PMCID
PMC2652503
Subset
IM
Grants
NIDDK NIH HHS · DK-58872 · United States
NIDDK NIH HHS · R01 DK073462-03 · United States
NIDDK NIH HHS · R01 DK058872 · United States
NHLBI NIH HHS · R01 HL051057 · United States
NIDDK NIH HHS · P01 DK055388 · United States
NIDDK NIH HHS · DK-55388 · United States
NIDDK NIH HHS · R01 DK073462 · United States
NHLBI NIH HHS · R01 HL051057-15 · United States
NHLBI NIH HHS · R01-HL51057 · United States
NIDDK NIH HHS · P01 DK055388-100002 · United States
Databases
GEO
GSE7396
Corrections
CommentIn
PMID: 19154711
CommentIn
PMID: 19789086
External Links
PubMed source DOI: 10.1016/j.devcel.2008.12.002 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2