Article
- The EMBO Journal (1999) 18, 6282 - 6289
- doi:10.1093/emboj/18.22.6282
Heme deficiency in erythroid lineage causes differentiation arrest and cytoplasmic iron overload
Osamu Nakajima1, Satoru Takahashi1, Hideo Harigae2, Kazumichi Furuyama2, Norio Hayashi2, Shigeru Sassa3 and Masayuki Yamamoto1
- Center for Tsukuba Advanced Research Alliance and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8577, Japan
- Department of Biochemistry, Tohoku University School of Medicine, 2-1 Seiryocho, Aoba-ku, Sendai 980-8575, Japan
- Laboratory of Biochemical Hematology, The Rockefeller University, 1230 York Avenue, New York, NY 10021-6399, USA
Correspondence to:
Masayuki Yamamoto, E-mail: masi@tara.tsukuba.ac.jp
Received 12 July 1999; Accepted 28 September 1999; Revised 28 September 1999
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.
Keywords:
- ALAS-E,
- heme,
- iron metabolism,
- transferrin receptors,
- X-linked sideroblastic anemia
