Differentiation of hematopoietic cells involves progressive restriction of developmental potential as pluripotent hematopoietic stem cells give rise to multipoten-tial progenitors that subsequently mature along single lineages. Although mechanisms responsible for decision-making in hematopoietic development are not defined, it is likely that they involve two distinct, but interrelated, pathways: one involving nuclear regulatory proteins that directly control and coordinate gene expression, and a second involving signal transduction from growth factors through their cognate surface receptors. One goal ofresearch efforts is identification of lineage-restricted nuclear regulatory proteins that establish the unique and characteristic gene expression profiles of mature hematopoietic cell types. In principle, searches for such factors might rely on finding cell-specific DNA-binding proteins characterized by the presence of sequence motifs found in known regulators in other systems (such as homedomains, zinc fingers, helix-loop-helix, or basic zipper motifs) or on discovering novel, putative transcription factor genes at the sites of chromosomal translocations in leukemias. An inherent difficulty with these approaches relates to ignorance regarding target genes acted on by these proteins and, hence, in appreciating the roles of putative regulators during normal cellular differentiation. The identification of nuclear DNA-binding proteins that recognize short DNA sequences in cis-regulatory elements associated with lineage-specific transcription offers an alternative and more direct route to relating controlling proteins and target genes. If proteins identified in this manner regulate sets of genes characteristic of a lineage, an understanding of the mechanisms of transcriptional control of the regulator itself provides a means of unravelling the first steps in the pathway of lineage development.

From this perspective, I will review evidence implicating transcription factors of a small family, the GATA-binding proteins, in control of gene expression and development of hematopoietic cells. Questions raised by recent studies are considered in relation to approaches that may provide definitive answers in the future.