Cell-specific mitotic defect and dyserythropoiesis associated with erythroid band 3 deficiency

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Abstract

Most eukaryotic cell types use a common program to regulate the process of cell division. During mitosis, successful partitioning of the genetic material depends on spatially coordinated chromosome movement and cell cleavage1. Here we characterize a zebrafish mutant, retsina (ret), that exhibits an erythroid-specific defect in cell division with marked dyserythropoiesis similar to human congenital dyserythropoietic anemia. Erythroblasts from ret fish show binuclearity and undergo apoptosis due to a failure in the completion of chromosome segregation and cytokinesis. Through positional cloning, we show that the ret mutation is in a gene (slc4a1) encoding the anion exchanger 1 (also called band 3 and AE1), an erythroid-specific cytoskeletal protein. We further show an association between deficiency in Slc4a1 and mitotic defects in the mouse. Rescue experiments in ret zebrafish embryos expressing transgenic slc4a1 with a variety of mutations show that the requirement for band 3 in normal erythroid mitosis is mediated through its protein 4.1R–binding domains. Our report establishes an evolutionarily conserved role for band 3 in erythroid-specific cell division and illustrates the concept of cell-specific adaptation for mitosis.

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Figure 1: Analysis of the phenotype associated with the ret mutation.
Figure 2: Analysis of the ret locus and expression pattern.
Figure 3: Functional analysis of the protein encoded by ret.
Figure 4: Role of band 3 in erythroid cytokinesis.
Figure 5: Erythroid cytokinesis defect in mouse and zebrafish band 3 mutants and structure–function relationship of mouse band 3 for rescuing anemia in ret embryos.

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Acknowledgements

We thank K. Dooley, C. Burns, D. Ransom, D. Traver, L. Washburn and C. Birkenmeier for critical review of the manuscript; P. Haffter and C. Nüsslein-Volhard for providing the WIK strain; C. Amemiya, A. Schier and W. Talbot for support and advice; S. Johnson for the DAR and SJD strains; M. Mueckler for SLC2A1 cDNA; M. Listewnik for assistance with the FISH experiments; and N. White and W. Saganic for the zebrafish husbandry. B.H.P. was supported by a Howard Hughes Medical Institutes Post-doctoral Fellowship for Physicians and the US National Institutes of Health. L.I.Z. is an Investigator of the Howard Hughes Medical Institutes. L.L.P. was supported by a US National Cancer Institute Cancer Core Grant to The Jackson Laboratory. The work was supported by funding from the US National Institutes of Health.

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Correspondence to Leonard I. Zon.

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Paw, B., Davidson, A., Zhou, Y. et al. Cell-specific mitotic defect and dyserythropoiesis associated with erythroid band 3 deficiency. Nat Genet 34, 59–64 (2003) doi:10.1038/ng1137

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