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1 Laboratory of Developmental Molecular Genetics, Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-Ku, Kyoto, 606-8501, Japan
2 Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA
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Abstract |
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 Top Abstract IntroductionResultsDiscussionExperimental proceduresReferences |
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Introduction |
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-aminolevulinate synthase (ALAS2), -aminolevulinic acid dehydratase (ALAD), porphobilinogen deaminase (PBGD), uroporphyrinogen III synthase (UROS), uroporphyrinogen decarboxylase (UROD), coproporphyrinogen oxidase (CPO), protoporphyrinogen oxidase (PPO) and ferrochelatase (FCH). All human heme synthesis enzymes have been cloned and their biochemical features in heme biosynthesis have been well characterized in vitro, but their expression patterns and roles in development have not been fully explored. In mammals, it is relatively difficult to access early developmental processes including primitive hematopoiesis because they occur within mother's body. Zebrafish and medaka fish are useful model organisms for studies of primitive erythropoiesis that is highly conserved between fish and mammals (Dooley & Zon 2000; Tanaka et al. 2004). Furthermore, recent chemical mutagenesis screening in both zebrafish and medaka have identified four mutants exhibiting defects in heme synthesis enzymes (ALAS2, ALAD UROD, and FCH) (Brownlie et al. 1998; Wang et al. 1998; Childs et al. 2000; Sakamoto et al. 2004). Zebrafish sauternes (sau) mutant displays delayed erythroid maturation with altered globin gene expression (Brownlie et al. 1998). sau encodes zebrafish ALAS2, representing the first animal model for congenital sideroblastic anemia. The medaka mutant white out (who) is a hypochromic anemia mutant and has elongated blood cells with little hemoglobin production (Sakamoto et al. 2004). who encodes ALAD (the second heme synthesis enzyme) and represents a model for human ALAD-deficiency porphyria. Zebrafish yquem (yqe) mutant has a deficiency in UROD (the fifth enzyme), resulting in a porphyria characterized by photosensitive, auto-fluorescent blood (Wang et al. 1998). The yqe/UROD mutant represents a zebrafish model for human hepatoerythropoietic porphyria. The zebrafish dracula (drc) phenotype is very similar to that of erythropoietic protoporphyria in humans (Childs et al. 2000) and is caused by a lesion in the eighth heme synthesis enzyme, FCH. Thus, the usefulness of the zebrafish and medaka mutants as models for human blood diseases such as anemia and porphyria is demonstrated by characterization of these hematopoietic mutants.
In zebrafish, primitive erythrogenesis occurs in the ICM that might be an equivalent to the extra-embryonic yolk sac blood island in mammals (Amatruda & Zon 1999). During zebrafish somitogenesis stages, cells forming bilateral stripes in the posterior lateral plate mesoderm (LPM) migrate to the midline and form the ICM. Several hematopoiesis specific transcriptional factors including gata1 and biklf are induced in the LPM before the expression of erythroid specific genes, including heme synthesis enzymes and globin genes (Detrich et al. 1995; Kawahara & Dawid 2000). The vlad tepes/gata1 mutation and injection of biklf antisense morpholino (biklf-MO) lead to the significant reduction of blood cells in zebrafish (Kawahara & Dawid 2001; Lyons et al. 2002) and therefore it is important to elucidate the nature of their target genes and the mechanism by which these factors regulate erythroid cell maturation.
We report here that the expression of CPO, responsible for the sixth step of heme biosynthesis, is strongly induced in the ICM during erythrogenesis. A knockdown of zebrafish CPO using CPO-MO led to a strong inhibition of hemoglobin production. Interestingly, the expression profiles of gata1, ße2- and ße3-globin genes are altered in the CPO-MO-injected embryos compared to those that are uninjected. Our finding that injection of human CPO (hCPO) rescued the hypochromia of CPO-MO-injected embryos indicates that CPO possesses an equivalent function in heme biosynthesis in zebrafish and humans. Finally, we demonstrate that both gata1 and biklf are important for the regulation of CPO expression in zebrafish.
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Results |
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Heme is a prosthetic group of numerous hemoproteins (oxidases, cytochromes, etc.) that are essential for both erythroid cells and nonerythroid cells (Ponka 1999). In our in situ-based screening to identify genes that are predominantly expressed in the ICM, we have isolated a gene that encodes the sixth heme biosynthetic enzyme CPO. As shown in Fig. 1A, zebrafish CPO protein reveals high similarity to hCPO (60% identity) (Martasek et al. 1994a; Taketani et al. 1994) and mouse CPO (59% identity) (Kohno et al. 1993) through its entire region, and the partial amino acid sequence available for Fugu CPO also shows a high homology (77% identical to the corresponding region); thus the sequence of CPO is conserved between fish and mammals. In humans, mis-sense mutations in CPO were found in hereditary coproporphyria (HCP) patients (Fig. 1A), and the CPO enzymatic activity of these mutant proteins produced in Escherichia coli (E. coli) is severely reduced (Fujita et al. 1994; Lamoril et al. 1995, 2001; Schreiber et al. 1997). The amino acid residues mutated in HCP patients are completely conserved from zebrafish to humans (Fig. 1A; red circles). To examine the developmental expression pattern of CPO, we performed whole-mount in situ hybridization. CPO is uniformly expressed at the one-cell stage (data not shown), indicating that CPO mRNA is deposited maternally. Ubiquitous expression of CPO is gradually decreased during blastula and gastrula stages, and localized expression of CPO in the LPM was first detected around the seven-somite stage (Fig. 1D; black arrowhead). CPO-expressing cells migrate toward the midline of the trunk (Fig. 1E,G), and CPO is significantly expressed in the ICM ventral of the notochord around 24 hours post-fertilization (hpf) (Fig. 1H; green arrowhead). After 26 hpf, CPO is detected in both circulating blood cells (Fig. 1I; red arrowhead) and posterior ICM (Fig. 1J; blue arrowhead). Thus, the sequence and expression pattern of CPO suggest that zebrafish CPO functions as heme synthesis enzyme in blood cells during zebrafish erythropoiesis.
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It is known that mammalian CPO is one of the rate-limiting steps downstream of ALAS2 in heme biosynthesis (Conder et al. 1991; Taketani et al. 2001). To examine the role of CPO in zebrafish embryogenesis, we inhibited CPO synthesis using anti-sense morpholinos (CPO-MO and CPO-MO2). Erythrocytes are predominantly produced during zebrafish primitive hematopoiesis (de Jong & Zon 2005). As shown in Fig. 2, the red color of blood cells could be observed clearly in the heart of uninjected and control-MO-injected embryos (Fig. 2A,B; red arrowhead), whereas the heart of CPO-MO-injected embryos was transparent (Fig. 2C; red arrowhead) in spite of the existence of circulating blood cells (see succeeding discussions). Visualization of hemoglobin content in blood cells by o-dianisidine staining showed potent inhibition of hemoglobin production in the CPO-MO-injected embryos (Fig. 2F; black arrowhead). This phenotype is very specific, because injection of a morpholino mismatched in five residues (CPO-5 m) had no effect, whereas a second nonoverlapping morpholino (CPO-MO2) generated the same phenotype as the original morpholino (Supplementary Fig. S1). Furthermore, the staining intensity of diaminofluorene (DAF) that detects the peroxidase activity of hemoglobin was significantly decreased in the CPO-MO-injected embryos (Fig. 2G–I), indicating that the CPO-MO-injected embryos show hypochromia. As erythrocyte maturation proceeds, blood cell nuclei become condensed and the cytoplasm is reduced (Weinstein et al. 1996; Brownlie et al. 1998). We often observed that CPO-MO-injected embryos contain a larger amount of cytoplasm and less condensed nuclei compared to the uninjected and control-MO-injected embryos at 80 hpf (Fig. 2J–L). In addition, we examined whether the number of blood cells is reduced in the CPO-MO-injected embryos. In contrast to the drastic reduction of hemoglobin production in these embryos, blood cells in approximately normal numbers were found to circulate in the CPO-MO-injected embryos (Supplementary movies). Thus, the CPO-MO-injected embryos show strongly reduced hemoglobin production without apparent reduction in the number of blood cells, indicating that zebrafish CPO is required for hemoglobin production.
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Because the sequence of CPO is conserved between zebrafish and humans, their biological activities are likely to be conserved as well. To test this prediction, we examined whether hCPO constructs can restore the CPO-MO-induced suppression of hemoglobin production. As shown in Fig. 3A, we prepared two hCPO constructs; one is full-length hCPO and the other is a CPO mutant lacking most of the CPO-conserved domain that is similar to the mutation found in a human HCP patient (Susa et al. 1998). Synthetic RNAs of hCPO constructs were co-injected with the CPO-MO into one-cell stage embryos, and the hemoglobin content in blood cells was examined in two-to-three day old embryos (Fig. 3B, Table 1). Hemoglobin production was largely recovered by injection of hCPO as visualized by direct inspection (Fig. 3B; red arrowhead) or o-dianisidine staining (Fig. 3B; black arrowhead). Thus, hCPO can supply the required enzymatic activity for heme biosynthesis in the zebrafish embryo. In contrast, co-injection of the hCPO mutant construct with CPO-MO could not rescue the defects in hemoglobin production (Fig. 3B and Table 1). These results show that the biological role of CPO is conserved between zebrafish and humans and suggest that CPO-MO-injected zebrafish could be a very useful in vivo assay system for estimating the biological activity of mutant forms of hCPO.
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To further examine the role of CPO during primitive erythrogenesis, we analyzed the effect of CPO-MO injection on the expression of erythroid specific genes 
e1-, ße2-, ße3-globins, gata1, biklf, and ALAS2. We observed no difference in their expression between uninjected and CPO-MO-injected embryos at 22 hpf (Fig. 4), suggesting that CPO does not affect their initial expression in erythroid cells. At 48 hpf, the expression of e1-globin, biklf and ALAS2 in the CPO-MO-injected embryos was also comparable to that in uninjected embryos (Fig. 4). In contrast, the expression of ße2-, ße3-globins and gata1 was maintained at a high level in the circulating blood cells of CPO-MO-injected embryos at this time (Fig. 4). In both fish and mammals, gata1 expression decreases during erythroid cell maturation (Brownlie et al. 1998; Zambidis et al. 2005). Our observations suggest that erythroid cell maturation is affected and possibly blocked by the suppression of CPO production in the morpholino injected embryos.
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Previous studies have shown that two erythroid-specific transcriptional factors, gata1 (GATA family) and biklf (Krüppel-like family), are required for erythroid cell differentiation in zebrafish (Kawahara & Dawid 2001; Lyons et al. 2002). Expression of both genes in the LPM starts before the expression of heme synthesis enzymes and globin genes are induced in the LPM. Interestingly, it has been reported that promoter regions of human heme synthesis enzymes and globin genes contain GATA-1 binding sites and CACCC motifs [cis-acting element of Krüppel-like factors including erythroid Krüppel-like factors (EKLF) and Biklf] (Miller & Bieker 1993; Delfau-Larue et al. 1994). These findings suggest that heme synthesis enzymes and globin genes are target genes for gata1 and biklf in zebrafish. To test the possibility, we examined the expression patterns of ALAS2, CPO, e1-globin in vlt/gata1 and biklf-MO-injected embryos at the 18-somite stage. As shown in Fig. 5, expression of these genes in the ICM was strongly reduced in the vlt/gata1 mutants. In the biklf-MO-injected embryos, ALAS2 was strongly inhibited, whereas CPO and e1-globin expression was reduced. Expression of all these genes was completely suppressed in vlt/gata1 mutant embryos that were injected with biklf-MO (Fig. 5). Furthermore, we found that CPO was strongly induced in gata1 plus biklf RNAs-injected embryos at shield stage (Fig. 6), whereas ectopic expression of CPO was weakly detected in the biklf RNA-injected embryos, but not in the gata1 RNA-injected embryos (Fig. 6), indicating that the combination of Gata1 and Biklf can activate the CPO gene at a premature stage (shield stage). We have designed a reporter construct [hCPO promoter- green fluorescent protein (GFP)] in which the hCPO promoter region (Tanabe et al. 1997) is connected to the coding sequence of GFP. This construct is functional in zebrafish because GFP expression was observed in the circulating blood cells in the hCPO promoter-GFP-injected embryos (data not shown). GFP expression could be stimulated by gata1 or biklf RNA and most effectively by a combination of both (Fig. 6). These results support the view that the expression of CPO is directly regulated through cooperative action of gata1 and biklf.
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Discussion |
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CPO has been proposed to be one of the rate-limiting enzymes in the heme biosynthesis pathway in mammals. As previously reported (Taketani et al. 2001), CPO plays an important role for hemoglobin production in human erythroleukemia K562 cells. However, it has not been clear whether CPO functions in erythroid cell maturation during early vertebrate embryogenesis in addition to its role in hemoglobin production. In this paper we showed that the sequences of zebrafish and hCPO are highly homologous, and that CPO is expressed during zebrafish embryogenesis in the ICM, where erythroid cells are generated. Knockdown of CPO using CPO-MO in zebrafish resulted in hypochromia that is a defect in hemoglobin production. Furthermore, the CPO-MO-mediated suppression of hemoglobin production is restored by injection of hCPO RNA, indicating that the functional role of CPO on heme synthesis is conserved between fish and humans. It is noteworthy that the color of blood cells is transparent in CPO-MO-injected embryos, but circulating blood cell number is comparable to that of uninjected embryos (Supplementary movies). It will be interesting to clarify whether knockdown of CPO affects erythroid cell maturation in any way beyond heme production. It is known that the nucleus of blood cells in fish is condensed and the cytoplasm is reduced in size during erythrogenesis (Weinstein et al. 1996; Brownlie et al. 1998). We often observed that the blood cells of CPO-MO-injected embryos contain less condensed nuclei and have larger cytoplasm compared to the uninjected embryos (Fig. 2J–L). Additionally, we found that the expression of ße2, ße3-globins and gata1 is maintained at a high level at 48 hpf in CPO-MO-injected embryos, whereas expression of these genes normally ceases by this time. In contrast, biklf, ALAS2, and e1-globin are not affected. In the zebrafish sau/ALAS2 mutant that has defects in hemoglobin production, gata1 expression is maintained at a high level compared to wild-type embryos (Brownlie et al. 1998). This phenotype is identical to that of the CPO-MO-injected embryo. Interestingly, there is a clear difference with respect to the ße2-globin expression; ße2-globin expression is down-regulated in sau/ALAS2 mutant as in wild-type embryos during erythrocyte maturation, whereas a high expression level of ße2-globin is maintained in CPO-MO-injected embryos. Further studies will be required to clarify the functional interaction between heme synthesis enzymes and globin genes. In this paper, we emphasize the fact that CPO is required for some aspects of normal erythroid differentiation as well as hemoglobin production in zebrafish. It has been shown that mutations in hCPO cause HCP (Delfau-Larue et al. 1994; Martasek et al. 1994b). The enzymatic activity of hCPO mutants is reduced as judged by in vitro enzymatic assays. Because there is a functional equivalence between zebrafish and hCPO in hemoglobin production during erythropoiesis and CPO mutant fish have not been identified so far, CPO-MO-injected embryos might be useful for studying the pathogenesis of CPO deficiency and molecular mechanism of human HCP in the context of vertebrate embryogenesis.
Transcriptional regulation of CPO by the erythroid-specific transcription factors Gata1 and Biklf
In this paper, we have shown that localized expression of zebrafish CPO during early embryogenesis is restricted to the ICM, a major site of primitive hematopoiesis. Heme synthesis enzymes, like globins, are strongly induced during the formation of erythroid cells. Recently, microarray analysis of the zebrafish cloche mutant that has defects in both hematopoiesis and vasculogenesis, led to the isolation of CPO as one of the genes that are down-regulated in cloche (Qian et al. 2005). Although the molecular nature of cloche remains to be elucidated, several transcription factors including Scl, c-Myc, c-Myb, Gata2 and Runx1 are known to regulate vertebrate hematopoiesis (Crosier et al. 2002; Berman et al. 2003). In zebrafish, both gata1 (GATA family) and biklf (Krüppel-like factor, related to human EKLF) (Donze et al. 1995; Kawahara & Dawid 2000) are restricted in the erythroid lineage and are required for primitive erythrogenesis (Kawahara & Dawid 2001; Kobayashi et al. 2001; Lyons et al. 2002). We found that the expression of heme synthesis enzymes (CPO and ALAS2) and the e1-globin gene is decreased in vlt/gata1 or biklf-MO-injected embryos. When the biklf-MO was injected into vlt/gata1 embryos, CPO expression was completely suppressed. These results suggest that Gata1 and Biklf cooperate in the regulation of CPO expression. A simple explanation would be that both Gata1 and Biklf can directly bind to a regulatory region of the CPO gene. It has been shown that GATA-1 regulates the expression of mouse CPO in an erythroid cell differentiation system of human erythroleukemia cells (Taketani et al. 2001). Furthermore, the upstream region containing both promoter and enhancer of hCPO (NT_086640
[GenBank]
) has several GATA and CACCC sites, and there are GATA and CACCC motifs in the putative promoter/enhancer region of CPO in the zebrafish genome (NW_634973). Injection of biklf RNA, but not gata1 RNA, weakly induced ectopic CPO expression, whereas co-injection of gata1 and biklf RNAs had a synergistic effect. Furthermore, co-injection of gata1 and biklf RNAs effectively activated a hCPO promoter construct in zebrafish embryos, supporting the view of a functional cooperation between Gata1 and Biklf in CPO gene regulation. Future analysis of promoter/enhancer elements of zebrafish CPO should provide more precise insights into mechanisms of CPO transcriptional regulation.
Determination of biologic activity of hCPO mutations using the CPO-MO-injected zebrafish embryo
Human CPO mutations (mis-sense and nonsense mutations) have been discovered in HCP patients and constitute the molecular basis for the observed phenotype. It is relatively difficult to measure the enzymatic activity of hCPO in heme biosynthesis using expression in E. coli and in vitro enzyme assays. We have shown that the biological activity of CPO constructs can be assayed in vivo using CPO-MO-injected zebrafish embryos. RNA transcripts corresponding to full-length or a deletion mutant corresponding to a CPO mutant in a HCP patient were injected together with CPO-MO into zebrafish embryos, and subsequent examination showed that full-length, but not the mutant hCPO construct was able to rescue the defects in hemoglobin production. This assay is quite easy and reproducible, and can be performed at relatively low cost, and may represent a new useful tool to measure the biologic activity of hCPO mutations from HCP patients.
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Experimental procedures |
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Digoxigenin (DIG)-labeled anti-sense RNA probes for in situ hybridization were prepared using RNA labeling kit (Roche). Embryos were hybridized at 65 °C overnight in hybridization buffer (50% formamide, 5 x SSC, 5 mM EDTA, 0.1% Tween-20, 50 µg/mL heparin, 1 mg/mL RNA torula). After hybridization, embryos were washed twice at 65 °C for 30 min with washing buffer I (50% formamide, 2 x SSC, 0.1% Tween 20), twice at 65 °C for 30 min in washing buffer II (2 x SSC, 0.1% Tween 20), twice at 65 °C for 30 min in washing buffer III (0.2 x SSC, 0.1% Tween 20), and finally incubated with maleic acid solution (0.1 M maleic acid pH 7.5) at room temperature (r.t.) for 15 min. After preincubation with blocking buffer (0.1 M maleic acid pH 7.5, 5% sheep serum, 2% blocking reagent) for 2 h, embryos were incubated with anti-DIG-alkaline phosphatase (Roche) in blocking buffer at r.t. for 4 h. Embryos were washed 6 times in phosphate buffered saline (PBS) containing 0.1% Tween-20 (PBST). Color reaction was carried out using BM purple (Roche) as substrate; staining was terminated by washing the embryos with PBS-Tween 20 (PBST), and then the embryos were fixed at 4 °C overnight in 4% paraformaldehyde.
Plasmid construction
To construct pCS2P(+)-hCPO, the SphI-SalI fragment (containing the entire coding region of hCPO) of pGEM-5Z-hCPO cDNA (a kind gift from Dr M. Daimon) was subcloned into pCS2P(+) vector. The DNA fragment encoding hCPO mutant (encoding truncated protein that is 175 amino acids) was amplified by polymerase chain reaction (PCR) using the hCPO cDNA and the following primers: 5'-CGGGATCCGCCGCCATGGCCTTGCAGCTGGGCAG-3' and 5'-GCTCTAGATCAGTTGGCGCCCCCGTCTACC-3'. The amplified fragment of hCPO mutant was digested by XbaI and BamHI, and was cloned into the pCS2P +vector (pCS2P-hCPO mutant). To construct hCPO promoter-GFP, the hCPO promoter region (from –786 to +1) (Tanabe et al. 1997) was fused to the GFP gene.
Synthetic RNA and morpholino oligonucleotides microinjection
Sense RNAs encoding full-length hCPO, hCPO mutant, gata1, and biklf were transcribed in vitro from pCS2P-hCPO, pCS2P-hCPO mutant, pCS2-gata1 (a kind gift from Dr M. Kobayashi) and pCS2-HA-biklf, respectively, using mMESSAGE mMACHINE kit (Ambion) according to the manufacturer's instructions. Synthetic RNAs were dissolved in injection buffer (40 mM HEPES [pH 7.4], 240 mM KCl, and 0.5% phenol red). RNAs (100 pg) were injected into the blastomere of one-cell stage zebrafish embryos. Morpholino oligonucleotides against zebrafish CPO (CPO-MO; 5'-GCACAAAGCTAACGAAGTCATGCTG-3' and CPO-MO2; 5'-TCTGCTGAGCGAACACGACGCAGTC-3') were obtained from Gene Tools, LLC. The nucleotides complementary to the initiation sites in the zebrafish CPO are underlined. Control-MO possesses an unrelated sequence that is supplied by the company and CPO-5 m (5'-GCAGAAAGGTAAGGAACTCAAGCTG-3') contains 5 mis-matched nucleotides compared to CPO. Morpholino oligonucleotide against zebrafish biklf (biklf-MO) has been previously described (Kawahara & Dawid 2001). CPO-MO (5 ng), CPO-MO2 (5 ng), CPO-5 m, Cont-MO or biklf-MO (5 ng) was injected into the yolk or the blastomeres of the 1–4 cell stage embryos.
Histological analysis and microscopic observation of circulating blood cells
Staining of hemoglobin by o-dianisidine was performed as previously described (Kawahara & Dawid 2001). DAF staining was performed to measure the peroxidase activity of hemoglobin (Weinstein et al. 1996). Dechorionated embryos were fixed overnight at 4 °C, washed three times with PBS, and preincubated in DAF staining solution (0.01% DAF, 200 mM Tris [pH 7.0], 0.05% Tween-20) about 1 h at r.t. in the dark. Hydrogen peroxide was added to a final concentration of 0.3%, and the embryos were incubated for 15 min. Giemsa staining was performed as previously described (Tanaka et al. 2004). Blood cells were collected after tail amputation. The blood cells were fixed in methanol on glass slides and then stained for 15 min with 10% Giemsa: methanol solution (Nacalai Tesque Chemical Co.). Circulating blood cells in wild-type, control-MO-injected and CPO-MO-injected living embryos (54 hpf stage) were scanned by the CSU22-MetaMorph system (OLYMPUS).
Mutants and wild-type zebrafish
Mutant alleles of vlad tepes (vlt)m651 (Weinstein et al. 1996) were used. Genotyping of vlt was performed as previously described (Lyons et al. 2002). Wild-type zebrafish of strain AB or Riken-Wako were used for injection assay.
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Acknowledgements |
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Data deposition: CPO sequence reported in this paper has been submitted to the GENBANK database (AB180841 [GenBank] ).
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Footnotes |
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* Correspondence: E-mail: atsuo{at}hmro.med.kyoto-u.ac.jp
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References |
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Berman, J., Hsu, K. & Look, A.T. (2003) Zebrafish as a model organism for blood diseases. Br. J. Haematol. 123, 568–576.[CrossRef][Medline]
Brownlie, A., Donovan, A., Pratt, S.J., et al. (1998) Positional cloning of the zebrafish sauternes gene: a model for congenital sideroblastic anaemia. Nature Genet. 20, 244–250.[CrossRef][Medline]
Childs, S., Weinstein, B.M., Mohideen, M.A., et al. (2000) Zebrafish dracula encodes ferrochelatase and its mutation provides a model for erythropoietic protoporphyria. Curr. Biol. 10, 1001–1004.[CrossRef][Medline]
der, L.H., Woodard, S.I. & Dailey, H.A. (1991) Multiple mechanisms for the regulation of haem synthesis during erythroid cell differentiation. Possible role for coproporphyrinogen oxidase. Biochem. J. 275, 321–326.[Medline]
Crosier, P.S., Kalev-Zylinska, M.L., Hall, C.J., et al. (2002) Pathways in blood and vessel development revealed through zebrafish genetics. Int. J. Dev. Biol. 46, 493–502.[Medline]
Delfau-Larue, M.H., Martasek, P. & Grandchamp, B. (1994) Coproporphyrinogen oxidase: gene organization and description of a mutation leading to exon 6 skipping. Hum. Mol. Genet.
3, 1325–1330.
Detrich, H.W., 3rd, Kieran, M.W.
Chan, , F.Y., et al. (1995) Intraembryonic hematopoietic cell migration during vertebrate development. Proc. Natl. Acad. Sci. USA
92, 10713–10717.
Donze, D., Townes, T.M. & Bieker, J.J. (1995) Role of erythroid Kruppel-like factor in human gamma- to beta-globin gene switching. J. Biol. Chem.
270, 1955–1959.
Dooley, K. & Zon, L.I. (2000) Zebrafish: a model system for the study of human disease. Curr. Opin. Genet. Dev. 10, 252–256.[CrossRef][Medline]
Fujita, H., Kondo, M., Taketani, S., et al. (1994) Characterization and expression of cDNA encoding coproporphyrinogen oxidase from a patient with hereditary coproporphyria. Hum. Mol. Genet.
3, 1807–1810.
Jong, J.L.O. & Zon, L.I. (2005) Use of the zebrafish system to study primitive and definitive hematopoiesis. Annu. Rev. Genet. 39, 481–501.[CrossRef][Medline]
Kawahara, A. & Dawid, I.B. (2000) Expression of the Krüppel-like zinc finger gene biklf during zebrafish development. Mech. Dev. 97, 173–176.[CrossRef][Medline]
Kawahara, A. & Dawid, I.B. (2001) Critical role of biklf in erythroid cell differentiation in zebrafish. Curr. Biol. 11, 1353–1357.[CrossRef][Medline]
Kobayashi, M., Nishikawa, K. & Yamamoto, M. (2001) Hematopoietic regulatory domain of gata1 gene is positively regulated by GATA1 protein in zebrafish embryos. Development 128, 2341–2350.[Medline]
Kohno, H., Furukawa, T., Yoshinaga, T., Tokunaga, R. & Taketani, S. (1993) Coproporphyrinogen oxidase: purification, molecular cloning, and induction of mRNA during erythroid differentiation. J. Biol. Chem.
268, 21359–21363.
Lamoril, J., Martasek, P., Deybach, J.C., et al. (1995) A molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria. Hum. Mol. Genet.
4, 275–278.
Lamoril, J., Puy, H., Whatley, S.D., et al. (2001) Characterization of mutations in the CPO gene in British patients demonstrates absence of genotype-phenotype correlation and identifies relationship between hereditary coproporphyria and harderoporphyria. Am. J. Hum. Genet. 68, 1130–1138.[CrossRef][Medline]
Lyons, S.E., Lawson, N.D., Lei, L., et al. (2002) A nonsense mutation in zebrafish gata1 causes the bloodless phenotype in vlad tepes. Proc. Natl. Acad. Sci. USA
99, 5454–5459.
Martasek, P., Camadro, J.M., Delfau-Larue, M.H., et al. (1994a) Molecular cloning, sequencing, and functional expression of a cDNA encoding human coproporphyrinogen oxidase. Proc. Natl. Acad. Sci. USA
91, 3024–3028.
Martasek, P., Nordmann, Y. & Grandchamp, B. (1994b) Homozygous hereditary coproporphyria caused by an arginine to tryptophane substitution in coproporphyrinogen oxidase and common intragenic polymorphisms. Hum. Mol. Genet.
3, 477–480.
Miller, I.J. & Bieker, J.J. (1993) A novel, erythroid cell-specific murine transcription factor that binds to the CACCC element and is related to the Kruppel family of nuclear proteins. Mol. Cell. Biol.
13, 2776–2786.
Ponka, P. (1999) Cell biology of heme. Am. J. Med. Sci. 318, 241–256.[CrossRef][Medline]
Qian, F., Zhen, F., Ong, C., et al. (2005) Microarray analysis of zebrafish cloche mutant using amplified cDNA and identification of potential downstream target genes. Dev. Dyn. 233, 1163–1172.[CrossRef][Medline]
Sakamoto, D., Kudo, H., Inohaya, K., et al. (2004) A mutation in the gene for delta-aminolevulinic acid dehydratase (ALAD) causes hypochromic anemia in the medaka, Oryzias latipes. Mech. Dev. 121, 747–752.[CrossRef][Medline]
Schreiber, W.E., Zhang, X., Senz, J. & Jamani, A. (1997) Hereditary coproporphyria: exon screening by heteroduplex analysis detects three novel mutations in the coproporphyrinogen oxidase gene. Hum. Mutat. 10, 196–200.[CrossRef][Medline]
Susa, S., Daimon, M., Yamamori, I., et al. (1998) A novel mutation of coproporphyrinogen oxidase (CPO) gene in a Japanese family. J. Hum. Genet. 43, 182–184.[CrossRef][Medline]
Taketani, S., Furukawa, T. & Furuyama, K. (2001) Expression of coproporphyrinogen oxidase and synthesis of hemoglobin in human erythroleukemia K562 cells. Eur. J. Biochem. 268, 1705–1711.[Medline]
Taketani, S., Kohno, H., Furukawa, T., Yoshinaga, T. & Tokunaga, R. (1994) Molecular cloning, sequencing and expression of cDNA encoding human coproporphyrinogen oxidase. Biochim. Biophys. Acta 1183, 547–549.[Medline]
Tanabe, A., Furukawa, T., Ogawa, Y., et al. (1997) Invovement of the transcriptional factor GATA-1 in regulation of expression of coproporphyrinogen oxidase in mouse erythroleukemia cells. Biochem. Biophys. Res. Commun. 233, 729–736.[CrossRef][Medline]
Tanaka, K., Ohisa, S., Orihara, N., et al. (2004) Characterization of mutations affecting embryonic hematopoiesis in the medaka, Oryzias latipes. Mech. Dev. 121, 739–746.[CrossRef][Medline]
Wang, H., Long, Q., Marty, S.D., Sassa, S. & Lin, S. (1998) A zebrafish model for hepatoerythropoietic porphyria. Nature Genet. 20, 239–243.[CrossRef][Medline]
Weinstein, B.M., Schier, A.F., Abdelilah, S., et al. (1996) Hematopoietic mutations in the zebrafish. Development 123, 303–309.[Abstract]
Zambidis, E.T., Peault, B., Park, T.S., Bunz, F. & Civin, C.I. (2005) Hematopoietic differentiation of human embryonic stem cells progresses through sequential hematoendothelial, primitive, and definitive stages resembling human yolk sac development. Blood
106, 860–870.
Received: 1 September 2005
Accepted: 27 November 2005
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