Transcription Factor Miz-1 Is Required to Regulate Interleukin-7 Receptor Signaling at Early Commitment Stages of B Cell Differentiation
Transcription Factor Miz-1 Is Required to Regulate Interleukin-7 Receptor Signaling at Early Commitment Stages of B Cell Differentiation
Kosan, C. et al. Immunity 33:917-928, 2010
Speaker: Tsung-Hao Chang (張琮浩) Time: 13:10-14:00, Apr. 13, 2011
Commentator: Dr. Pin Ling (凌斌 老師) Place: Room 601
Abstract
B cell development requires the coordination of multiple control mechanisms including the expression of specific transcription factors and cytokine signaling. During B cell development, common lymphoid progenitors (CLPs) sequentially differentiate into pre-pro B cells (Fraction A), pro-B cells (Fraction B/C), pre-B cells (Fraction D), immature B cells and mature B cells1. Cells in these stages can be identified by several specific surface markers. However, the molecular mechanisms of B cell development still remain largely unclear. The Miz-1 (Zbtb17) gene encodes an 87 kDatranscription factor. The authors generated a Miz-1 loss-of-function mutant mouse model by deleting its DNA binding domain, the POZ (Poxvirus and zinc finger) domain. This loss-of-function mutation resulted in a defect in lymphocyte development as determined by using the Vav-cre-loxPsystem, a conditional knockout model in hematopoietic lineage. The blockade of B cell development at pro-B cell stage (B220+CD43+HSA+BP-1-CD19+) in Vav-cre Zbtb17fl/fl mice was confirmed by flow cytometry. Furthermore, high level of apoptosis was observed in Vav-cre Zbtb17fl/fl pro-B cells. Pro-survival IL-7 signaling was impaired in Vav-cre Zbtb17fl/fl CLPs by the higher expression levels of a negative regulator in IL-7 signaling, Socs1. The direct binding of Miz-1 to Socs1 promoter was confirmed by ChIP assay. Moreover, down-regulation of Ebf1, an essential transcription factor in B cell development2, was observed in Vav-cre Zbtb17fl/fl CLPs. Ectopic expression of both Bcl-2 and Ebf1 could partially restore B cell differentiation from the Vav-cre Zbtb17fl/fl progenitors. In conclusion, the authors have determined the roles of Miz-1 in controlling both cell apoptosis by direct binding to Socs1 promoter and differentiation by regulating Ebf1 expression during B cell development.
References:
1. Nagasawa, T. Microenvironmental niches in the bone marrow required for B-cell development. Nat. Rev. Immunol. 6:107-116, 2006.
2. Northrup, D.L., and Allman, D. Transcriptional regulation of early B cell development. Immunol. Res. 42:106–117, 2008.