ELUCIDATING REGULATORY NETWORKS PROMOTING B-CELL DEVELOPMENT

B-cells are an essential part of our adaptive immune system. A network of transcription factors together with external signals facilitate the gradual developmental progression from progenitor cells towards the B-cell fate. Several key factors participating in this network have been identified. Among these are the transcription factors E2A, HEB, EBF1 and FOXO1 as well as the IL7 signaling cascade. The objective of this thesis has been to increase our understanding of the transcriptional network orchestrating B-lineage specification and commitment. Based on the combined expression of surface markers and transgenic reporter genes, we have identified three hierarchically related and functionally distinct subpopulations within the common lymphoid progenitor (CLP) compartment. Using this knowledge, we have re-evaluated previously characterized knock-out mouse models in order to obtain a higher resolution analysis of critical events in early B-cell commitment. Based on these studies, we propose a transcriptional hierarchy where the transcription factors E2A and HEB initiate the B-cell specification program in the LY6D- CLPs through up regulation of FOXO1. During the transition to LY6D expressing CLPs, E2A and FOXO1 induce EBF1. Subsequently, FOXO1 and EBF1 generate a feed-forward loop, leading to activation of PAX5, B-cell commitment and the progression to the CD19+ pro-B cell stage