Regulation of B cell fate determination by EBF (83.7)

Abstract

Abstract B cell fate specification is associated with the expression of genes encoding components of the B cell antigen receptor and the ordered rearrangement of the immunoglobulin heavy-chain locus. Accompanying activation of the early program of B lineage gene expression is the concerted repression of lineage inappropriate genes. EBF is a transcription factor expressed exclusively in the B lineage and evidence is mounting that it is the limiting factor directing the B cell fate choice. To gain insight into mechanisms of EBF directed B cell fate specification, we generated EBF−/− cell lines. The cell surface phenotype, growth factor requirements, gene expression profile, and in vivo functional capabilities of EBF−/− clonal cell lines is consistent with a lymphoid-biased multipotential progenitor. To identify and discriminate novel EBF target genes involved in B cell fate specification, we performed comparative gene expression profiling of EBF−/−, Pax-5−/−, and RAG2−/− cell lines. ANOVA analysis of variance revealed that the EBF−/− lines overexpress several genes associated with early hematopoietic differentiation and stem cell function, notably a subset of HoxA genes. Conversely, the EBF−/− cells are defective in expression of a subset of early B lineage genes including lymphocyte enhancer factor-1, LEF-1. Consistent with the deficiency in LEF-1, EBF−/− lines display elevated levels of fas and increased sensitivity to apoptosis. Taken together, these data suggest novel regulatory circuits involving EBF during B cell fate specification, including inhibition of HoxA genes and activation of the Wnt signaling pathway.