title: Heme deficiency in erythroid lineage causes differentiation arrest and cytoplasmic iron overload.
abstract: Erythroid 5-aminolevulinate synthase (ALAS-E) catalyzes the first step of heme biosynthesis in erythroid cells. Mutation of human ALAS-E causes the disorder X-linked sideroblastic anemia. To examine the roles of heme during hematopoiesis, we disrupted the mouse ALAS-E gene. ALAS-E-null embryos showed no hemoglobinized cells and died by embryonic day 11.5, indicating that ALAS-E is the principal isozyme contributing to erythroid heme biosynthesis. In the ALAS-E-null mutant embryos, erythroid differentiation was arrested, and an abnormal hematopoietic cell fraction emerged that accumulated a large amount of iron diffusely in the cytoplasm. In contrast, we found typical ring sideroblasts that accumulated iron mostly in mitochondria in adult mice chimeric for ALAS-E-null mutant cells, indicating that the mode of iron accumulation caused by the lack of ALAS-E is different in primitive and definitive erythroid cells. These results demonstrate that ALAS-E, and hence heme supply, is necessary for differentiation and iron metabolism of erythroid cells.
authors.affiliation: Center for Tsukuba Advanced Research Alliance and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8577, USA.
authors.forename: O
authors.initials: O
authors.lastname: Nakajima
authors.forename: S
authors.initials: S
authors.lastname: Takahashi
authors.forename: H
authors.initials: H
authors.lastname: Harigae
authors.forename: K
authors.initials: K
authors.lastname: Furuyama
authors.forename: N
authors.initials: N
authors.lastname: Hayashi
authors.forename: S
authors.initials: S
authors.lastname: Sassa
authors.forename: M
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D002678:Chimera; D003593:Cytoplasm / Q000378:metabolism / Q000648:ultrastructure; D005314:Embryonic and Fetal Development; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000648:ultrastructure; D004920:Erythropoiesis / Q000235:genetics*; D005260:Female; D005313:Fetal Death; D005434:Flow Cytometry; D005838:Genotype; D006418:Heme / Q000172:deficiency*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D007527:Isoenzymes; D006418:Heme; D007501:Iron; D000624:5-Aminolevulinate Synthetase