Tim-2 is the receptor for H-ferritin on oligodendrocytes.
Oligodendrocytes stain more strongly for iron than any other cell in the CNS, and they require iron for the production of myelin. For most cell types transferrin is the major iron delivery protein, yet neither transferrin receptor protein nor mRNA are detectable in mature oligodendrocytes. Thus an alternative iron delivery mechanism must exist. Given the significant long term consequences of developmental iron deficiency and the iron requirements for normal myelination, identification of the iron delivery mechanism for oligodendrocytes is important. Previously we have reported that oligodendrocytes bind H-ferritin and that H-ferritin binds to white matter tracts in vivo. Recently, T cell immunoglobulin and mucin domain-containing protein-2 (Tim-2) was shown to bind and internalize H-ferritin. In the present study we show that Tim-2 is expressed on oligodendrocytes both in vivo and in vitro. Further, the onset of saturable H-ferritin binding in CG4 oligodendrocyte cell line is accompanied by Tim-2 expression. Application of a blocking antibody to the extracellular domain of Tim-2 significantly reduces H-ferritin binding to the differentiated CG4 cells and primary oligodendrocytes. Tim-2 expression on CG4 cells is responsive to iron; decreasing with iron loading and increasing with iron chelation. Taken together, these data provide compelling evidence that Tim-2 is the H-ferritin receptor on oligodendrocytes suggesting it is the primary mechanism for iron acquisition by these cells.
Todorich
Bozho
B
Department of Neurosurgery, Penn State College of Medicine, Hershey, PA 17033-0850, USA.
Zhang
Xuesheng
X
Slagle-Webb
Becky
B
Seaman
William E
WE
Connor
James R
JR
D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D001052:Apoferritins / Q000378:metabolism*; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007501:Iron / Q000494:pharmacology; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009836:Oligodendroglia / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017262:Siderophores / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology
D000906:Antibodies; D005904:Glial Fibrillary Acidic Protein; D008565:Membrane Proteins; D017262:Siderophores; C442242:Timd2 protein, mouse; D001052:Apoferritins; D007501:Iron; D003676:Deferoxamine