Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver
Hiromi Gunshin, … , Sylvie Robine, Nancy C. Andrews
Hiromi Gunshin, … , Sylvie Robine, Nancy C. Andrews
Published May 2, 2005
Citation Information: J Clin Invest. 2005;115(5):1258-1266. https://doi.org/10.1172/JCI24356.
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Article Hematology

Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver

Abstract

Solute carrier family 11, member 2 (SLC11A2) is the only transmembrane iron transporter known to be involved in cellular iron uptake. It is widely expressed and has been postulated to play important roles in intestinal iron absorption, erythroid iron utilization, hepatic iron accumulation, placental iron transfer, and other processes. Previous studies have suggested that other transporters might exist, but their physiological significance remained uncertain. To define the activities of Slc11a2 in vivo, we inactivated the murine gene that encodes it globally and selectively. We found that fetal Slc11a2 is not needed for materno-fetal iron transfer but that Slc11a2 activity is essential for intestinal non-heme iron absorption after birth. Slc11a2 is also required for normal hemoglobin production during the development of erythroid precursors. However, hepatocytes and most other cells must have an alternative, as-yet-unknown, iron uptake mechanism. We previously showed that Slc11a2 serves as the primary portal for intestinal iron entry in hemochromatosis. However, inactivation of murine Hfe ameliorates the phenotype of animals lacking Slc11a2.

Authors

Hiromi Gunshin, Yuko Fujiwara, Angel O. Custodio, Cristina DiRenzo, Sylvie Robine, Nancy C. Andrews

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Targeted disruption of Slc11a2. Slc11a2 wild-type locus (A) and targeted...
Targeted disruption of Slc11a2. Slc11a2 wild-type locus (A) and targeted locus (B). The targeting construct contained herpes simplex virus thymidine kinase gene (HSV-TK) and neomycin-resistance (Neo) and cytidine deaminase (CD) cassettes. Homologous recombination removed exons 6–8, replacing them with neomycin-resistance and cytidine deaminase cassettes flanked by loxP sites (triangles). The 5′ and 3′ probes used for Southern blot analysis are shown as red bars labeled A and B, respectively. F, forward; R, reverse. Southern blot analysis of clones using the 3′ probe (C) and the 5′ probe (D). Clones 1, 4, and 5 were correct at both ends. La, ladder. (E) Analysis of tissue iron content in female Slc11a2+/– and wild-type mice. (F) Wild-type and Slc11a2–/– (arrow) neonates on day 1 of life. Slc11a2–/– mice were pale and runted. (G) PCR analysis of DNA prepared from duodenum (D), kidney (K), and liver (L) from Slc11a2–/– and wild-type mice using primer set F and R shown in A and B. Morphology of peripheral blood smears from wild-type (H) and Slc11a2–/– (I) mice. Original magnification, ×40. The mutant mice had hypochromic, microcytic cells with marked anisocytosis and poikilocytosis. Perls Prussian blue iron staining of wild-type neonatal liver (J) and Slc11a2–/– neonatal liver (K). Original magnification, ×100. There was little iron deposition in hepatocytes and Kupffer cells (arrows) of wild-type mice but marked iron deposition in those of Slc11a2–/– mice following a single intraperitoneal injection of iron dextran (5 mg iron).