IL-7R-dependent survival and differentiation of early T-lineage progenitors is regulated by the BTB/POZ domain transcription factor Miz-1.
T cells originate from early T lineage precursors that have entered the thymus and differentiate through well-defined steps. Mice deficient for the BTB/POZ domain of zinc finger protein-1 (Miz-1) almost entirely lack early T lineage precursors and have a CD4(-)CD8(-) to CD4(+)CD8(+) block causing a strong reduction in thymic cellularity. Miz-1(ΔPOZ) pro-T cells cannot differentiate in vitro and are unable to relay signals from the interleukin-7R (IL-7R). Both STAT5 phosphorylation and Bcl-2 up-regulation are perturbed. The high expression levels of SOCS1 found in Miz-1(ΔPOZ) cells probably cause these alterations. Moreover, Miz-1 can bind to the SOCS1 promoter, suggesting that Miz-1 deficiency causes a deregulation of SOCS1. Transgenic overexpression of Bcl-2 or inhibition of SOCS1 restored pro-T cell numbers and their ability to differentiate, supporting the hypothesis that Miz-1 is required for the regulation of the IL-7/IL-7R/STAT5/Bcl-2 signaling pathway by monitoring the expression levels of SOCS1.
Institut de recherches cliniques de Montréal, Montréal, QC, Canada.
Ingrid
I
Saba
Christian
C
Kosan
Lothar
L
Vassen
Tarik
T
Möröy
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics* / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D054503:Lymphoid Progenitor Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary; D020395:Receptors, Interleukin-7 / Q000502:physiology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D016335:Zinc Fingers / Q000235:genetics
D051741:Kruppel-Like Transcription Factors; D020395:Receptors, Interleukin-7; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; C107961:ZBTB17 protein, human