Transcription Factor GATA1 Is Dispensable for Mast Cell Differentiation in Adult Mice

Abstract

Although previous studies have shown that GATA1 is required for mast cell differentiation, the effects of the complete ablation of GATA1 in mast cells have not been examined. Using conditional Gata1 knockout mice (Gata1(-/y)), we demonstrate here that the complete ablation of GATA1 has a minimal effect on the number and distribution of peripheral tissue mast cells in adult mice. The Gata1(-/y) bone marrow cells were capable of differentiating into mast cells ex vivo. Microarray analyses showed that the repression of GATA1 in bone marrow mast cells (BMMCs) has a small impact on the mast cell-specific gene expression in most cases. Interestingly, however, the expression levels of mast cell tryptases in the mouse chromosome 17A3.3 were uniformly reduced in the GATA1 knockdown cells, and GATA1 was found to bind to a 500-bp region at the 5' end of this locus. Revealing a sharp contrast to that observed in the Gata1-null BMMCs, GATA2 deficiency resulted in a significant loss of the c-Kit(+) FcεRIα(+) mast cell fraction and a reduced expression of several mast cell-specific genes. Collectively, GATA2 plays a more important role than GATA1 in the regulation of most mast cell-specific genes, while GATA1 might play specific roles in mast cell functions.

GATA2 is critical for the maintenance of cellular identity in differentiated mast cells derived from mouse bone marrow

“…As reported previously, 4 the fraction of DP cells was decreased over time to only 7.9 6 1.5% of the initial amount on day 9 ( Figure 1A). Phase-contrast photomicrographs of the BMMCs on day 10 showed that the DCF/DCF BMMCs were irregular in size and shape compared with the CreER T2 control BMMCs ( Figure 1B).…”

“…[5][6][7] Interestingly, however, inducible deletion of GATA2 DNA-binding domain C-finger (CF) in BMMCs resulted in a significant reduction in the number of the c-Kit/ FceRIa double-positive (DP) cells, whereas the deletion of GATA1 did not significantly affect the frequency of DP cells or the cell morphology or viability. 4 These results suggest that GATA2 plays a more important role than GATA1 for maintaining the mast cell identity in BMMCs. In addition to GATA1 and GATA2, several other transcription factors including microphthalmia-associated transcription factor (MITF), runt related transcription factor 1 (RUNX1), T cell acute lymphocytic leukemia 1, and spleen focus forming virus (SFFV) proviral integration oncogene (PU.1) have been demonstrated to be involved in mast cell development.…”

“…We previously reported that both factors contribute to the expression of mast cell-specific genes. 4 Thus, we consider that the differences might be due to the residual GATA1 activity.…”

“…Recently, we reported that conditional ablation of GATA1 in adult mice exhibited a minimal effect on the cell number and distribution of peripheral tissue mast cells. 4 Quantitative chromatin immunoprecipitation (qChIP) assays and silent interfering RNA-mediated knockdown experiments revealed that both GATA1 and GATA2 regulate the expression of a series of known GATA factor downstream genes in BMMCs. [5][6][7] Interestingly, however, inducible deletion of GATA2 DNA-binding domain C-finger (CF) in BMMCs resulted in a significant reduction in the number of the c-Kit/ FceRIa double-positive (DP) cells, whereas the deletion of GATA1 did not significantly affect the frequency of DP cells or the cell morphology or viability.…”

GATA1 Is a Sensitive and Specific Nuclear Marker for Erythroid and Megakaryocytic Lineages

“…1 Using tissue-specific knockouts, GATA1 expression is necessary for the development of eosinophils and basophils but not mast cells. [10][11][12] In humans, germline mutations of GATA1, although rare, can result in varying degrees of anemia and thrombocytopenia. For instance, in X-linked dyserythropoietic anemia and thrombocytopenia, heterozygous mutation of GATA1 p.V205M abrogates the interaction with friend of GATA protein 1 (FOG1), resulting in anemia and thrombocytopenia with aberrant morphology of the platelets.…”