TRANSCRIPTION FACTOR GATA-3 IS REQUIRED FOR DEVELOPMENT OF THE T-CELLLINEAGE

THE zinc-finger transcription factor GATA-3 is expressed in haematopoi etic cells and in the developing kidney and nervous system(1-7). Withi n the haematopoietic lineages, expression of GATA-3 is restricted to t hymocytes and T cells. Functionally important GATA-3 binding sites hav e been identified in multiple T-cell-specific genes(1,6-8). Mice conta ining homozygous null mutations of the GATA-3 gene die on embryonic da y 12, precluding a detailed assessment of the role of GATA-3 in haemat opoietic development(9). Here we have used murine embryonic stem (ES) cells containing homozygous mutations in the GATA-3 gene (GATA-3(-/-)) in conjunction with the RAG-2(-/-) (ref. 10) and C57BL/6 complementat ion systems to study the role of GATA-3 in mammalian haematopoiesis. O ur results show that GATA-3(-/-) ES cells can contribute to the develo pment of the mature erythroid, myelomonocytic and B-cell lineages, but fail to give rise to thymocytes or mature peripheral T cells. The dif ferentiation of GATA-3(-/-) T cells is blocked at or before the earlie st double-negative (CD4(-)/CD8(-)) stage of thymocyte development, suc h that the GATA-3(-/-) ES cells are unable to contribute measurably to the double-negative thymocyte population. These findings suggest that GATA-3 is an essential and specific regulator of early thymocyte deve lopment.