Transcription Factor Miz-1 Is Required to Regulate Interleukin-7 Receptor Signaling at Early Commitment Stages of B Cell Differentiation

SummaryB cell development requires the coordinated action of transcription factors and cytokines, in particular interleukin-7 (IL-7). We report that mice lacking the POZ (Poxvirus and zinc finger) domain of the transcription factor Miz-1 (Zbtb17ΔPOZ/ΔPOZ) almost entirely lacked follicular B cells, as shown by the fact that their progenitors failed to activate the Jak-Stat5 pathway and to upregulate the antiapoptotic gene Bcl2 upon IL-7 stimulation. We show that Miz-1 exerted a dual role in the interleukin-7 receptor (IL-7R) pathway by directly repressing the Janus kinase (Jak) inhibitor suppressor of cytokine signaling 1 (Socs1) and by activating Bcl2 expression. Zbtb17ΔPOZ/ΔPOZ (Miz-1-deficient) B cell progenitors had low expression of early B cell genes as transcription factor 3 (Tcf3) and early B cell factor 1 (Ebf1) and showed a propensity for apoptosis. Only the combined re-expression of Bcl2 and Ebf1 could reconstitute the ability of Miz-1-deficient precursors to develop into CD19+ B cells.

Graphical AbstractFigure optionsDownload high-quality image (145 K)Download as PowerPoint slideHighlights
► Miz-1 is required for early B cell development
► Miz-1 directly represses the Jak (Janus kinase) inhibitor Socs1
► Miz-1 is required to upregulate Bcl2 upon IL-7 stimulation