HEMATOPOIESIS AND STEM CELLS Differential use of SCL/TAL-1 DNA-binding domain in developmental hematopoiesis

Dissecting the molecular mechanisms used by developmental regulators is es-sential to understand tissue specification/ differentiation. SCL/TAL-1 is a basic helix-loop-helix transcription factor absolutely critical for hematopoietic stem/progeni-tor cell specification and lineage matura-tion. Using in vitro and forced expression experimental systems, we previously sug-gested that SCL might have DNA-binding– independent functions. Here, to assess the requirements for SCL DNA-binding activity in vivo, we examined hematopoi-etic development in mice carrying a germ-line DNA-binding mutation. Remarkably, in contrast to complete absence of hema-topoiesis and early lethality in scl-null embryos, specification of hematopoietic cells occurred in homozygous mutant embryos, indicating that direct DNA bind-ing is dispensable for this process. Lethal-ity was forestalled to later in develop-ment, although some mice survived to adulthood. Anemia was documented throughout development and in adult-hood. Cellular and molecular studies showed requirements for SCL direct DNA binding in red cell maturation and indi-cated that scl expression is positively autoregulated in terminally differentiating erythroid cells. Thus, different mecha-nisms of SCL’s action predominate de-pending on the developmental/cellular context: indirect DNA binding activities and/or sequestration of other nuclear regulators are sufficient in specification processes, whereas direct DNA binding functions with transcriptional autoregula-tion are critically required in terminal maturation processes. (Blood. 2008;112: 1056-1067