Molecular Mechanism of Erythroid Differentiation

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We have investigated the special roles of erythroid type transcription factors, such as GATA-1 and NF-E2, on erythroid cell differentiation with special reference to heme biosynthesis. When expressions of erythroid specific delta-Aminolevulinate synthase (ALAS-E) in mouse erythroleukemia (MEL) cells was disturbed by anti-sense technique, expressions of every enzymes for heme biosynthesis pathway decreaded possibly due to decline in NF-E2 (Meguro et al., 1996) . This ovservation is in good agreement with previous results in DMSO-resistant clone of MEL cells (Fujita et al., 1991) .Then, we constructed ES cells lacking ALAS-E gene. The cells expressed almost same amount of GATA-1 and NF-E2 when compared with wild type cells. The cells, however, cannot accumulate heme, benzidine positive cells, and beta-major globin mRNAs after undergoing erythroid differentiation (Haigae et al., 1998) . Thus, it is obvious that ALAS-E mediated heme biosynthesis regulates erythroid differentiation not only through transcription activity of NF-E2 (Nagai et al, 1998) but also through mature type globin synthesis during late stage of erythroid differentiation.It is also demonstrated that mice lacking p18 subunit of NF-E2 was lethal. Using testis specific promoter, GATA-1 knock down mice was also obtained. The knock down mice was also lethal, however, analyzes of fetus indicated a marked decline in hemoglobinized cells.As far as we examined nonspecific delta-aminolevulinate synthase (ALAS-N), the gene was negatively regulated via NF-KB binding sequence (Fujita, 1998) .