B cell development is a carefully orchestrated process involving many transcription factors acting in concert with cytokine signals, particularly IL-7. The transcription factor c-Myb has long been implicated in B cell development, however surprisingly little is known about the function of c-Myb in B cell progenitors. I have used several mouse models of c-Myb deficiency to investigate the role of c-Myb in the B cell lineage. Conditional deletion of c-Myb in early B cell progenitors using mb-1Cre (c MybΔmb1/Δmb1) leads to a striking lack of B cells from the pre-pro-B cell stage onwards, demonstrating that c-Myb is absolutely required for B cell development. Mice homozygous for a hypomorphic allele of c-Myb (c MybPlt4/Plt4) also display a severe reduction in B cells; in these mice, defects in lymphoid development can be detected within the multipotent progenitor compartment of bone marrow. c-Myb activates transcription via coactivator proteins, particularly CBP and p300. Mice bearing a point mutation in p300 (p300Plt6/Plt6) that inhibits the interaction of p300 with c Myb display a partial block in B cell development, highlighting the importance of the c Myb-p300 complex for B cell development. Together, these mice demonstrate that c-Myb regulates B cell development by functioning both in multipotent progenitor cells and directly in B cell progenitors. In addition, I show that the B-lymphopenia in c-Myb deficient mice is related to a profound defect in IL-7 signalling. IL-7 normally stimulates the proliferation, survival and differentiation of B cell progenitors, however pro-B cells from c-MybPlt4/Plt4 and c MybΔmb1/Δmb1 mice fail to respond to IL 7. Expression of the IL-7Rα chain is reduced on pro-B cells from c MybPlt4/Plt4 and c-MybΔmb1/Δmb1 mice, suggesting that Il7r may be a c-Myb target gene in B cells. Reporter gene assays show that c-Myb can activate the Il7r promoter in synergy with the transcription factor Pu.1. Overall, this work demonstrates that c-Myb is essential for early B cell development and plays a critical role in linking cytokine signals to the transcription factor networks in B cell progenitors.
| Identifer | oai:union.ndltd.org:ADTP/245696 |
| Date | January 2009 |
| Creators | Greig, K. T. |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
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