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The Ufm1-activating enzyme Uba5 is indispensable for erythroid differentiation in mice.

Tatsumi K, Yamamoto-Mukai H, Shimizu R, Waguri S, Sou YS, Sakamoto A, Taya C, Shitara H, Hara T, Chung CH, Tanaka K, Yamamoto M, Komatsu M - Nat Commun (2011)

Bottom Line: In this study, we report the essential role of Uba5, a specific activating enzyme for the ubiquitin-like modifier, Ufm1, in erythroid development.Although Uba5 was dispensable for the production of erythropoietin, its genetic loss led to impaired development of megakaryocyte and erythroid progenitors from common myeloid progenitors.Our results suggest that one of the ubiquitin-like protein modification systems, the Ufm1 system, is involved in the regulation of haematopoiesis.

View Article: PubMed Central - PubMed

Affiliation: Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Kamikitazawa 2-1-6, Setagaya-ku, Tokyo 156-8506, Japan.

ABSTRACT
Post-translational protein modifications are systems designed to expand restricted genomic information through functional conversion of target molecules. Ubiquitin-like post-translational modifiers regulate numerous cellular events through their covalent linkages to target protein(s) by an enzymatic cascade analogous to ubiquitylation consisting of E1 (activating), E2 (conjugating) and E3 (ligating) enzymes. In this study, we report the essential role of Uba5, a specific activating enzyme for the ubiquitin-like modifier, Ufm1, in erythroid development. Mice lacking Uba5 exhibited severe anaemia, followed by death in utero. Although Uba5 was dispensable for the production of erythropoietin, its genetic loss led to impaired development of megakaryocyte and erythroid progenitors from common myeloid progenitors. Intriguingly, transgenic expression of Uba5 in the erythroid lineage rescued the Uba5-deficient embryos from anaemia and prolonged their survival, demonstrating the importance of Uba5 in cell-autonomous erythroid differentiation. Our results suggest that one of the ubiquitin-like protein modification systems, the Ufm1 system, is involved in the regulation of haematopoiesis.

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Correction of anaemia in Uba5-deficient mice by expression of Uba5 in erythroid lineage.(a) Embryonic morphology of Uba5 rescue mice. Representative photographs of Uba5+/+;TgUba5 and Uba5−/−;TgUba5 embryos at various embryonic stages. Scale bar, 2 mm. (b) Haematoxylin and eosin-stained fetal liver sections of Uba5+/+;TgUba5 and Uba5−/−;TgUba5 mice at E11.5. Scale bars: left panel, 1 mm; right panel, 20 μm. (c) Number of erythroid cells in fetal livers of Uba5+/+;TgUba5 and Uba5−/−;TgUba5 mice at E11.5. Data are means±s.d. of five mice from each group. (d) Wright–Giemsa-stained samples of peripheral blood cytospin cells prepared from control and rescued mice at E11.5. Scale bar, 20 μm. (e) Percentage of abnormal erythrocytes shown in d. Data are means±s.d. of five mice in each group.
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f3: Correction of anaemia in Uba5-deficient mice by expression of Uba5 in erythroid lineage.(a) Embryonic morphology of Uba5 rescue mice. Representative photographs of Uba5+/+;TgUba5 and Uba5−/−;TgUba5 embryos at various embryonic stages. Scale bar, 2 mm. (b) Haematoxylin and eosin-stained fetal liver sections of Uba5+/+;TgUba5 and Uba5−/−;TgUba5 mice at E11.5. Scale bars: left panel, 1 mm; right panel, 20 μm. (c) Number of erythroid cells in fetal livers of Uba5+/+;TgUba5 and Uba5−/−;TgUba5 mice at E11.5. Data are means±s.d. of five mice from each group. (d) Wright–Giemsa-stained samples of peripheral blood cytospin cells prepared from control and rescued mice at E11.5. Scale bar, 20 μm. (e) Percentage of abnormal erythrocytes shown in d. Data are means±s.d. of five mice in each group.

Mentions: Uba5+/− mice were crossed with G1HRD-Uba5 transgenic mice to generate mice that expressed Uba5 in the erythroid lineage (Uba5−/−;TgUba5, hereafter referred to as Uba5-rescue mice). All Uba5-rescue mouse embryos were alive at E13.5, in contrast to the death in utero of Uba5-deficient embryos at the same stage (Table 2), and were morphologically indistinguishable from control mice (Fig. 3a). However, the rescue mouse embryos appeared smaller than their control littermates at E15.5 and died by E18.5 (Fig. 3a and Table 2). Importantly, the hypoplasia observed in Uba5-deficient fetal livers (see Fig. 1a,b) was significantly ameliorated by the specific expression of Uba5 in the erythroid lineage (Fig. 3a,b and Supplementary Fig. S5a). The abnormal multinucleated erythrocytes that were detected in the fetal liver or peripheral blood of Uba5−/− embryos were not observed in the rescue embryos (Fig. 3b,d and Supplementary Fig. S5a).


The Ufm1-activating enzyme Uba5 is indispensable for erythroid differentiation in mice.

Tatsumi K, Yamamoto-Mukai H, Shimizu R, Waguri S, Sou YS, Sakamoto A, Taya C, Shitara H, Hara T, Chung CH, Tanaka K, Yamamoto M, Komatsu M - Nat Commun (2011)

Correction of anaemia in Uba5-deficient mice by expression of Uba5 in erythroid lineage.(a) Embryonic morphology of Uba5 rescue mice. Representative photographs of Uba5+/+;TgUba5 and Uba5−/−;TgUba5 embryos at various embryonic stages. Scale bar, 2 mm. (b) Haematoxylin and eosin-stained fetal liver sections of Uba5+/+;TgUba5 and Uba5−/−;TgUba5 mice at E11.5. Scale bars: left panel, 1 mm; right panel, 20 μm. (c) Number of erythroid cells in fetal livers of Uba5+/+;TgUba5 and Uba5−/−;TgUba5 mice at E11.5. Data are means±s.d. of five mice from each group. (d) Wright–Giemsa-stained samples of peripheral blood cytospin cells prepared from control and rescued mice at E11.5. Scale bar, 20 μm. (e) Percentage of abnormal erythrocytes shown in d. Data are means±s.d. of five mice in each group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3105337&req=5

f3: Correction of anaemia in Uba5-deficient mice by expression of Uba5 in erythroid lineage.(a) Embryonic morphology of Uba5 rescue mice. Representative photographs of Uba5+/+;TgUba5 and Uba5−/−;TgUba5 embryos at various embryonic stages. Scale bar, 2 mm. (b) Haematoxylin and eosin-stained fetal liver sections of Uba5+/+;TgUba5 and Uba5−/−;TgUba5 mice at E11.5. Scale bars: left panel, 1 mm; right panel, 20 μm. (c) Number of erythroid cells in fetal livers of Uba5+/+;TgUba5 and Uba5−/−;TgUba5 mice at E11.5. Data are means±s.d. of five mice from each group. (d) Wright–Giemsa-stained samples of peripheral blood cytospin cells prepared from control and rescued mice at E11.5. Scale bar, 20 μm. (e) Percentage of abnormal erythrocytes shown in d. Data are means±s.d. of five mice in each group.
Mentions: Uba5+/− mice were crossed with G1HRD-Uba5 transgenic mice to generate mice that expressed Uba5 in the erythroid lineage (Uba5−/−;TgUba5, hereafter referred to as Uba5-rescue mice). All Uba5-rescue mouse embryos were alive at E13.5, in contrast to the death in utero of Uba5-deficient embryos at the same stage (Table 2), and were morphologically indistinguishable from control mice (Fig. 3a). However, the rescue mouse embryos appeared smaller than their control littermates at E15.5 and died by E18.5 (Fig. 3a and Table 2). Importantly, the hypoplasia observed in Uba5-deficient fetal livers (see Fig. 1a,b) was significantly ameliorated by the specific expression of Uba5 in the erythroid lineage (Fig. 3a,b and Supplementary Fig. S5a). The abnormal multinucleated erythrocytes that were detected in the fetal liver or peripheral blood of Uba5−/− embryos were not observed in the rescue embryos (Fig. 3b,d and Supplementary Fig. S5a).

Bottom Line: In this study, we report the essential role of Uba5, a specific activating enzyme for the ubiquitin-like modifier, Ufm1, in erythroid development.Although Uba5 was dispensable for the production of erythropoietin, its genetic loss led to impaired development of megakaryocyte and erythroid progenitors from common myeloid progenitors.Our results suggest that one of the ubiquitin-like protein modification systems, the Ufm1 system, is involved in the regulation of haematopoiesis.

View Article: PubMed Central - PubMed

Affiliation: Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Kamikitazawa 2-1-6, Setagaya-ku, Tokyo 156-8506, Japan.

ABSTRACT
Post-translational protein modifications are systems designed to expand restricted genomic information through functional conversion of target molecules. Ubiquitin-like post-translational modifiers regulate numerous cellular events through their covalent linkages to target protein(s) by an enzymatic cascade analogous to ubiquitylation consisting of E1 (activating), E2 (conjugating) and E3 (ligating) enzymes. In this study, we report the essential role of Uba5, a specific activating enzyme for the ubiquitin-like modifier, Ufm1, in erythroid development. Mice lacking Uba5 exhibited severe anaemia, followed by death in utero. Although Uba5 was dispensable for the production of erythropoietin, its genetic loss led to impaired development of megakaryocyte and erythroid progenitors from common myeloid progenitors. Intriguingly, transgenic expression of Uba5 in the erythroid lineage rescued the Uba5-deficient embryos from anaemia and prolonged their survival, demonstrating the importance of Uba5 in cell-autonomous erythroid differentiation. Our results suggest that one of the ubiquitin-like protein modification systems, the Ufm1 system, is involved in the regulation of haematopoiesis.

Show MeSH
Related in: MedlinePlus