Genetic networks dictating early lymphoid lineage decision events

Sammanfattning: Differentiation from hematopoietic stem cells to mature blood cells of different lineages is a continuous process that requires the coordinated activity of several stage and lineage specific transcription factors. These factors act in a transcriptional hierarchy and also in a combinatorial manner to establish the expression of the genes that comprise a specific differentiation program. The progression of hematopoietic progenitors to the earliest committed B cells is highly dependent of the transcription factor Early B-cell Factor (EBF). In the absence of this factor, B-cell development is arrested at the earliest pre-pro-B-cell stage, while all the other blood cell lineages appear to develop normally. To gain further insight in how B-lineage commitment is achieved we have investigated control elements and factors affecting the expression and functional activity of EBF. The identification and cloning of a promoter region flanking the EBF gene revealed that EBF is controlled by auto-regulation and provided additional support for the existence of a transcription factor hierarchy in early B cell development. We have also examined how signaling through the surface receptor Notch affects EBF activity. It is well established that Notch signaling is involved in early lineage decision events, promoting T- on behalf of B-cell differentiation. One important property of Notch in this course of events seems to be its ability to perturb the functional activity of EBF. Moreover, Notch signaling has the capacity to alter fate of already committed B-cells towards T-lineage, even though this feature is rare and only observed in the earliest pre-pro-B cells.