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Eosinophils from Lineage-Ablated dblGATA Bone Marrow Progenitors: The dblGATA Enhancer in the Promoter of GATA-1 Is Not Essential for Differentiation Ex Vivo¹

Kimberly D. Dyer^2,*, Meggan Czapiga, Barbara Foster^*, Paul S. Foster, Elizabeth M. Kang, Courtney M. Lappas, Jennifer M. Moser^*, Nora Naumann, Caroline M. Percopo^*, Steven J. Siegel^*, Jonathan M. Swartz^*, SukSee Ting-De Ravin and Helene F. Rosenberg^*

^* Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH), Bethesda, MD 20892; Research Technologies Branch, NIAID/NIH, Bethesda, MD 20892; School of Biomedical Sciences, University of Newcastle, Newcastle, New South Wales, Australia; and Laboratory of Host Defenses, NIAID/NIH, Bethesda, MD 20892

A critical role for eosinophils in remodeling of allergic airways was observed in vivo upon disruption of the dblGATA enhancer that regulates expression of GATA-1, which resulted in an eosinophil-deficient phenotype in the dblGATA mouse. We demonstrate here that bone marrow progenitors isolated from dblGATA mice can differentiate into mature eosinophils when subjected to cytokine stimulation ex vivo. Cultured dblGATA eosinophils contain cytoplasmic granules with immunoreactive major basic protein and they express surface Siglec F and transcripts encoding major basic protein, eosinophil peroxidase, and GATA-1, -2, and -3 to an extent indistinguishable from cultured wild-type eosinophils. Fibroblast coculture and bone marrow cross-transplant experiments indicate that the in vivo eosinophil deficit is an intrinsic progenitor defect, and remains unaffected by interactions with stromal cells. Interestingly, and in contrast to those from the wild type, a majority of the GATA-1 transcripts from cultured dblGATA progenitors express a variant GATA-1 transcript that includes a first exon (1E_B), located 3700 bp downstream to the previously described first exon found in hemopoietic cells (1E_A) and 42 bp upstream to another variant first exon, 1E_C. These data suggest that cultured progenitors are able to circumvent the effects of the dblGATA ablation by using a second, more proximal, promoter and use this mechanism to generate quantities of GATA-1 that will support eosinophil growth and differentiation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institute of Allergy and Infectious Diseases Division of Intramural Research.

² Address correspondence and reprint requests to Dr. Kimberly D. Dyer, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases/National Institutes of Health, 10 Center Drive, Building 10 Room 11C216, Bethesda, MD 20892-1883. E-mail address: kdyer{at}niaid.nih.gov

³ Abbreviations used in this paper: MBP, major basic protein; DAPI, 4', 6-diamidino-2-phenylindole dihydrochloride; EPO, eosinophil peroxidase; Fpr1, formyl peptide receptor 1.