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BioMetals

, Volume 28, Issue 3, pp 473–480 | Cite as

The use of hypotransferrinemic mice in studies of iron biology

  • Julia T. Bu
  • Thomas B. Bartnikas
Article
  • 227 Downloads

Abstract

The hypotransferrinemic (hpx) mouse is a model of inherited transferrin deficiency that originated several decades ago in the BALB/cJ mouse strain. Also known as the hpx mouse, this line is almost completely devoid of transferrin, an abundant serum iron-binding protein. Two of the most prominent phenotypes of the hpx mouse are severe anemia and tissue iron overload. These phenotypes reflect the essential role of transferrin in iron delivery to bone marrow and regulation of iron homeostasis. Over the years, the hpx mouse has been utilized in studies on the role of transferrin, iron and other metals in a variety of organ systems and biological processes. This review summarizes the lessons learned from these studies and suggests possible areas of future exploration using this versatile yet complex mouse model.

Keywords

Transferrin Mouse Hypotransferrinemia Iron Metal Hpx 

Notes

Acknowledgments

T.B.B. is supported by NIH R00DK084122.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Bartnikas TB, Fleming MD (2012) Hemojuvelin is essential for transferrin-dependent and transferrin-independent hepcidin expression in mice. Haematologica 97:189–192CrossRefPubMedCentralPubMedGoogle Scholar
  2. Bartnikas TB, Andrews NC, Fleming MD (2011) Transferrin is a major determinant of hepcidin expression in hypotransferrinemic mice. Blood 117:630–637CrossRefPubMedCentralPubMedGoogle Scholar
  3. Beard JL, Wiesinger JA, Li N, Connor JR (2005) Brain iron uptake in hypotransferrinemic mice: influence of systemic iron status. J Neurosci Res 79:254–261CrossRefPubMedGoogle Scholar
  4. Bernstein SE (1987) Hereditary hypotransferrinemia with hemosiderosis, a murine disorder resembling human atransferrinemia. J Lab Clin Med 110:690–705PubMedGoogle Scholar
  5. Bradbury MW, Raja K, Ueda F (1994) Contrasting uptakes of 59Fe into spleen, liver, kidney and some other soft tissues in normal and hypotransferrinaemic mice. Influence of an antibody against the transferrin receptor. Biochem Pharmacol 47:969–974CrossRefPubMedGoogle Scholar
  6. Buys SS, Martin CB, Eldridge M et al (1991) Iron absorption in hypotransferrinemic mice. Blood 78:3288–3290PubMedGoogle Scholar
  7. Canonne-Hergaux F, Levy JE, Fleming MD et al (2001) Expression of the DMT1 (NRAMP2/DCT1) iron transporter in mice with genetic iron overload disorders. Blood 97:1138–1140CrossRefPubMedGoogle Scholar
  8. Craven CM, Alexander J, Eldridge M et al (1987) Tissue distribution and clearance kinetics of non-transferrin-bound iron in the hypotransferrinemic mouse: a rodent model for hemochromatosis. Proc Natl Acad Sci USA 84:3457–3461CrossRefPubMedCentralPubMedGoogle Scholar
  9. Dickinson TK, Connor JR (1994) Histological analysis of selected brain regions of hypotransferrinemic mice. Brain Res 635:169–178CrossRefPubMedGoogle Scholar
  10. Dickinson TK, Connor JR (1995) Cellular distribution of iron, transferrin, and ferritin in the hypotransferrinemic (Hp) mouse brain. J Comp Neurol 355:67–80CrossRefPubMedGoogle Scholar
  11. Dickinson TK, Connor JR (1998) Immunohistochemical analysis of transferrin receptor: regional and cellular distribution in the hypotransferrinemic (hpx) mouse brain. Brain Res 801:171–181CrossRefPubMedGoogle Scholar
  12. Dickinson TK, Devenyi AG, Connor JR (1996) Distribution of injected iron 59 and manganese 54 in hypotransferrinemic mice. J Lab Clin Med 128:270–278CrossRefPubMedGoogle Scholar
  13. Djeha A, Pérez-Arellano JL, Hayes SL et al (1995) Cytokine-mediated regulation of transferrin synthesis in mouse macrophages and human T lymphocytes. Blood 85:1036–1042PubMedGoogle Scholar
  14. Ganz T (2013) Systemic iron homeostasis. Physiol Rev 93:1721–1741CrossRefPubMedGoogle Scholar
  15. Ghio AJ, Carter JD, Richards JH et al (2000) Diminished injury in hypotransferrinemic mice after exposure to a metal-rich particle. Am J Physiol Lung Cell Mol Physiol 278:L1051–L1061PubMedGoogle Scholar
  16. Gkouvatsos K, Papanikolaou G, Pantopoulos K (2012) Regulation of iron transport and the role of transferrin. Biochim Biophys Acta 1820:188–202CrossRefPubMedGoogle Scholar
  17. Herrera C, Pettiglio MA, Bartnikas TB (2014) Investigating the role of transferrin in the distribution of iron, manganese, copper, and zinc. J Biol Inorg Chem 19:869–877CrossRefPubMedGoogle Scholar
  18. Huggenvik JI, Craven CM, Idzerda RL et al (1989) A splicing defect in the mouse transferrin gene leads to congenital atransferrinemia. Blood 74:482–486PubMedGoogle Scholar
  19. Iancu TC, Shiloh H, Raja KB et al (1995) The hypotransferrinaemic mouse: ultrastructural and laser microprobe analysis observations. J Pathol 177:83–94CrossRefPubMedGoogle Scholar
  20. Jenkitkasemwong S, Wang C-Y, Mackenzie B, Knutson MD (2012) Physiologic implications of metal-ion transport by ZIP14 and ZIP8. Biometals 25:643–655CrossRefPubMedGoogle Scholar
  21. Johnson MB, Enns CA (2004) Diferric transferrin regulates transferrin receptor 2 protein stability. Blood 104:4287–4293CrossRefPubMedGoogle Scholar
  22. Kaplan J, Craven C, Alexander J et al (1988) Regulation of the distribution of tissue iron. Lessons learned from the hypotransferrinemic mouse. Ann N Y Acad Sci 526:124–135CrossRefPubMedGoogle Scholar
  23. Kautz L, Jung G, Valore EV et al (2014) Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet 46:678–684CrossRefPubMedCentralPubMedGoogle Scholar
  24. Lederman M, Obolensky A, Grunin M et al (2012) Retinal function and structure in the hypotransferrinemic mouse. Invest Ophthalmol Vis Sci 53:605–612CrossRefPubMedGoogle Scholar
  25. Levy JE, Jin O, Fujiwara Y et al (1999) Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat Genet 21:396–399CrossRefPubMedGoogle Scholar
  26. Macedo MF, de Sousa M, Ned RM et al (2004) Transferrin is required for early T-cell differentiation. Immunology 112:543–549CrossRefPubMedCentralPubMedGoogle Scholar
  27. Malecki EA, Buhl KM, Beard JL et al (2000) Bone structural and mechanical properties are affected by hypotransferrinemia but not by iron deficiency in mice. J Bone Miner Res 15:271–277CrossRefPubMedGoogle Scholar
  28. Mastrogiannaki M, Matak P, Peyssonnaux C (2013) The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions. Blood 122:885–892CrossRefPubMedCentralPubMedGoogle Scholar
  29. McKie AT, Marciani P, Rolfs A et al (2000) A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 5:299–309CrossRefPubMedGoogle Scholar
  30. McKie AT, Barrow D, Latunde-Dada GO et al (2001) An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291:1755–1759CrossRefPubMedGoogle Scholar
  31. Mizutani K, Toyoda M, Mikami B (2012) X-ray structures of transferrins and related proteins. Biochim Biophys Acta 1820:203–211CrossRefPubMedGoogle Scholar
  32. Nam H, Wang C-Y, Zhang L et al (2013) ZIP14 and DMT1 in the liver, pancreas, and heart are differentially regulated by iron deficiency and overload: implications for tissue iron uptake in iron-related disorders. Haematologica 98:1049–1057CrossRefPubMedCentralPubMedGoogle Scholar
  33. Patel N, Masaratana P, Diaz-Castro J et al (2012) BMPER protein is a negative regulator of hepcidin and is up-regulated in hypotransferrinemic mice. J Biol Chem 287:4099–4106CrossRefPubMedCentralPubMedGoogle Scholar
  34. Patel N, Varghese J, Masaratana P et al (2014) The transcription factor ATOH8 is regulated by erythropoietic activity and regulates HAMP transcription and cellular pSMAD1,5,8 levels. Br J Haematol 164:586–596CrossRefPubMedCentralPubMedGoogle Scholar
  35. Radunović A, Ueda F, Raja KB et al (1997) Uptake of 26-Al and 67-Ga into brain and other tissues of normal and hypotransferrinaemic mice. Biometals 10:185–191CrossRefPubMedGoogle Scholar
  36. Raja KB, Simpson RJ, Peters TJ (1994) Intestinal iron absorption studies in mouse models of iron-overload. Br J Haematol 86:156–162CrossRefPubMedGoogle Scholar
  37. Raja KB, Simpson RJ, Peters TJ (1995) Assessment of intestinal blood-flux by laser Doppler fluxmetry in mice with altered intestinal iron absorption. Br J Haematol 89:874–879CrossRefPubMedGoogle Scholar
  38. Raja KB, Pountney DJ, Simpson RJ, Peters TJ (1999) Importance of anemia and transferrin levels in the regulation of intestinal iron absorption in hypotransferrinemic mice. Blood 94:3185–3192PubMedGoogle Scholar
  39. Raja KB, Jafri SE, Peters TJ, Simpson RJ (2006) Iron and cadmium uptake by duodenum of hypotransferrinaemic mice. Biometals 19:547–553CrossRefPubMedGoogle Scholar
  40. Robb A, Wessling-Resnick M (2004) Regulation of transferrin receptor 2 protein levels by transferrin. Blood 104:4294–4299CrossRefPubMedGoogle Scholar
  41. Simpson RJ, Lombard M, Raja KB et al (1991a) Iron absorption by hypotransferrinaemic mice. Br J Haematol 78:565–570CrossRefPubMedGoogle Scholar
  42. Simpson RJ, Raja KB, Halliwell B et al (1991b) Iron speciation in hypotransferrinaemic mouse serum. Biochem Soc Trans 19:317SPubMedGoogle Scholar
  43. Simpson RJ, Cooper CE, Raja KB et al (1992) Non-transferrin-bound iron species in the serum of hypotransferrinaemic mice. Biochim Biophys Acta 1156:19–26CrossRefPubMedGoogle Scholar
  44. Simpson RJ, Konijn AM, Lombard M et al (1993) Tissue iron loading and histopathological changes in hypotransferrinaemic mice. J Pathol 171:237–244CrossRefPubMedGoogle Scholar
  45. Takeda A, Devenyi A, Connor JR (1998) Evidence for non-transferrin-mediated uptake and release of iron and manganese in glial cell cultures from hypotransferrinemic mice. J Neurosci Res 51:454–462CrossRefPubMedGoogle Scholar
  46. Takeda A, Takatsuka K, Connor JR, Oku N (2001) Abnormal iron accumulation in the brain of neonatal hypotransferrinemic mice. Brain Res 912:154–161CrossRefPubMedGoogle Scholar
  47. Takeda A, Takatsuka K, Connor JR, Oku N (2002) Abnormal iron delivery to the bone marrow in neonatal hypotransferrinemic mice. Biometals 15:33–36CrossRefPubMedGoogle Scholar
  48. Tanno T, Bhanu NV, Oneal PA et al (2007) High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 13:1096–1101CrossRefPubMedGoogle Scholar
  49. Tanno T, Porayette P, Sripichai O et al (2009) Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood 114:181–186CrossRefPubMedCentralPubMedGoogle Scholar
  50. Trenor CC, Campagna DR, Sellers VM et al (2000) The molecular defect in hypotransferrinemic mice. Blood 96:1113–1118PubMedGoogle Scholar
  51. Ueda F, Raja KB, Simpson RJ et al (1993) Rate of 59Fe uptake into brain and cerebrospinal fluid and the influence thereon of antibodies against the transferrin receptor. J Neurochem 60:106–113CrossRefPubMedGoogle Scholar
  52. Wang C-Y, Knutson MD (2013) Hepatocyte divalent metal-ion transporter-1 is dispensable for hepatic iron accumulation and non-transferrin-bound iron uptake in mice. Hepatology 58:788–798CrossRefPubMedGoogle Scholar
  53. Weinstein DA, Roy CN, Fleming MD et al (2002) Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood 100:3776–3781CrossRefPubMedGoogle Scholar
  54. Yang F, Coalson JJ, Bobb HH et al (1999) Resistance of hypotransferrinemic mice to hyperoxia-induced lung injury. Am J Physiol 277:L1214–L1223PubMedGoogle Scholar
  55. Yang F, Wang X, Haile DJ et al (2002) Iron increases expression of iron-export protein MTP1 in lung cells. Am J Physiol Lung Cell Mol Physiol 283:L932–L939CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineBrown UniversityProvidenceUSA

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