Abstract
We have identified expression of the gene encoding the transcriptional coactivator FOG-1 (Friend of GATA-1; Zfpm1, Zinc finger protein multitype 1) in B lymphocytes. We found that FOG-1 expression is directly or indirectly dependent on the B cell-specific coactivator OBF-1 and that it is modulated during B cell development: expression is observed in early but not in late stages of B cell development. To directly test in vivo the role of FOG-1 in B lymphocytes, we developed a novel embryonic stem cell recombination system. For this, we combined homologous recombination with the FLP recombinase activity to rapidly generate embryonic stem cell lines carrying a Cre-inducible transgene at the Rosa26 locus. Using this system, we successfully generated transgenic mice where FOG-1 is conditionally overexpressed in mature B-cells or in the entire hematopoietic system. While overexpression of FOG-1 in B cells did not significantly affect B cell development or function, we found that enforced expression of FOG-1 throughout all hematopoietic lineages led to a reduction in the number of circulating eosinophils, confirming and extending to mammals the known function of FOG-1 in this lineage.
Highlights
The development of specialized hematopoietic cells from selfrenewing hematopoietic stem cells proceeds through a number of precursor stages with progressively restricted differentiation potential and requires a complex interplay of transcription factors and epigenetic modifiers
Friend of GATA-1 (FOG-1), which is encoded by the Zfpm1 (Zinc finger protein multitype 1) gene, was previously thought to be expressed primarily in cells of the erythroid and megakaryocytic lineages, where it is essential for differentiation [3,4]
Identification of FOG-1 expression in B cells In previous studies from our laboratory microarray analysis had been used to determine expression profiles of Pre-B-cells lacking the transcriptional coactivator OBF-1 [23,24] and transgenic thymocytes overexpressing OBF-1; these experiments identified several genes that were downregulated in null cells [25] or upregulated in overexpressing cells [25,26]
Summary
The development of specialized hematopoietic cells from selfrenewing hematopoietic stem cells proceeds through a number of precursor stages with progressively restricted differentiation potential and requires a complex interplay of transcription factors and epigenetic modifiers. These regulators are responsible for orchestrating the establishment of lineage-specific gene expression patterns that underlie cellular differentiation (reviewed in [1,2]). Friend of GATA-1 (FOG-1), which is encoded by the Zfpm (Zinc finger protein multitype 1) gene, was previously thought to be expressed primarily in cells of the erythroid and megakaryocytic lineages, where it is essential for differentiation [3,4]. FOG-1 is essential for specific branches of the haematopoietic system, and its inappropriate expression leads to abnormal cell differentiation
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