Id1 attenuates Notch signaling and impairs T-cell commitment by elevating Deltex1 expression.
Complete inhibition of E protein transcription factors by Id1 blocks the developmental transition of CD4/CD8 double-negative 1 (DN1; CD44(+) CD25(-)) thymocytes to the DN2 (CD44(+) CD25(+)) stage. To understand the underlying mechanisms, we observed that mRNA levels of Deltex1, as well as Deltex4, were dramatically elevated in Id1-expressing thymocytes, which could result in developmental arrest by attenuating Notch function. In support of this hypothesis, we found that Deltex1 ablation enabled Id1-expressing progenitors to differentiate to the DN3 (CD44(-) CD25(+)) stage, which was accompanied by enhanced Notch1 expression in T-cell progenitors. Consistently, constitutive activation of Notch1 drove the differentiation of Id1-expressing progenitors to the DN3 stage. Furthermore, we showed that Gfi1b levels decreased, whereas GATA3 levels increased in Id1 transgenic thymocytes. When overexpressed, GATA3 was able to upregulate Deltex1 transcription. Thus, T-cell commitment may be controlled by the interplay among E proteins, Gfi1b, and GATA3 transcription regulators, which influence Notch function through the expression of Deltex1.
Wang
Hong-Cheng
HC
Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
Perry
S Scott
SS
Sun
Xiao-Hong
XH
D000818:Animals; D017690:Cell Transplantation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism*; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases
D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; C497455:Idb1 protein, mouse; C508022:Il2rb protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D053646:Interleukin-2 Receptor beta Subunit; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C104035:Dtx1 protein, mouse; D044767:Ubiquitin-Protein Ligases