Transcription factor miz-1 is required to regulate interleukin-7 receptor signaling at early commitment stages of B cell differentiation

Immunity. 2010 Dec 14;33(6):917-28. doi: 10.1016/j.immuni.2010.11.028.

Abstract

B 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 (Zbtb17(ΔPOZ/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. Zbtb17(ΔPOZ/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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • B-Lymphocytes / pathology
  • Bone Marrow / pathology*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Lineage / genetics
  • Cell Lineage / immunology
  • Cell Survival / genetics
  • Cells, Cultured
  • Mice
  • Mice, Mutant Strains
  • Mutation / genetics
  • Nuclear Proteins / genetics
  • Nuclear Proteins / immunology
  • Nuclear Proteins / metabolism*
  • Protein Inhibitors of Activated STAT / genetics
  • Protein Inhibitors of Activated STAT / immunology
  • Protein Inhibitors of Activated STAT / metabolism*
  • Receptors, Interleukin-7 / genetics
  • Receptors, Interleukin-7 / immunology
  • Receptors, Interleukin-7 / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Ubiquitin-Protein Ligases
  • bcl-Associated Death Protein / biosynthesis*
  • bcl-Associated Death Protein / genetics
  • bcl-Associated Death Protein / immunology

Substances

  • Nuclear Proteins
  • Protein Inhibitors of Activated STAT
  • Receptors, Interleukin-7
  • bcl-Associated Death Protein
  • Miz1 protein, mouse
  • Ubiquitin-Protein Ligases