An HMG-box-containing T-cell factor required for thymocyte differentiation

Abstract

Two candidate genes for controlling thymocyte differentiation, T-cell factor-1 (Tcf-1) and lymphoid enhancer-binding factor (Lef-1), encode closely related DNA-binding HMG-box proteins. Their expression pattern is complex and largely overlapping during embryogenesis, yet restricted to lymphocytes postnatally. Here we generate two independent germline mutations in Tcf-1 and find that thymocyte development in (otherwise normal) mutant mice is blocked at the transition from the CD8+, immature single-positive to the CD4+/CD8+ double-positive stage. In contrast to wild-type mice, most of the immature single-positive cells in the mutants are not in the cell cycle and the number of immunocompetent T cells in peripheral lymphoid organs is reduced. We conclude that Tcf-1 controls an essential step in thymocyte differentiation.

Analysis of Transcription Factor Expression during Discrete Stages of Postnatal Thymocyte Differentiation

“…2). In Tcf1 mutant mice (36), differentiation is impaired just before the DP stage, a stage at which our data indicate that Tcf1 is up-regulated (Table I). Consistencies were also noted between our data and published findings for Egrs (37) c-Myb (38), GATA-3 (39), Lmo1 (40), Heb (41), Runx1 (42), and many others.…”

Notch and Wnt signaling in T-lymphocyte development and acute lymphoblastic leukemia

“…Two different Tcf-1 mutant mice have been described, targeting either exon 5 (Tcf-1(V)) or exon 7 (Tcf-1(VII)). 85 In Tcf-1(V) mutant mice, a low level of a truncated yet functional Tcf-1 is still expressed, whereas the Tcf-1(VII) mutation abolishes the DNA-binding activity of Tcf-1 completely and is therefore regarded as a true Tcf-1 null mutant. Young Tcf-1-deficient mice have an incomplete block at the DN1, DN2 and ISP stages, whereas older mice display a complete block at the DN1 stage of thymocyte development.…”

“…Young Tcf-1-deficient mice have an incomplete block at the DN1, DN2 and ISP stages, whereas older mice display a complete block at the DN1 stage of thymocyte development. 85,86 Although Lef-1 knockouts have normal T-cell development, 87 Lef-1/Tcf-1(V) double-deficient mice display a complete block in T-cell differentiation at the ISP stage, 88 showing the redundancy of these factors during thymocyte development.…”

G1/S transcriptional networks modulated by the HOX11/TLX1 oncogene of T-cell acute lymphoblastic leukemia

“…To further investigate this observation, we next performed luciferase reporter assays in 293 T cells using the TOPflash luciferase reporter plasmid. Transcription of the luciferase gene in the TOPflash plasmid is under the control of a transcription factor complex consisting of members of the T-cell factor (TCF)/lymphoid enhancer factor (LEF) family of DNA-binding molecules associated with stabilized b-catenin (Verbeek et al, 1995;Gounari et al, 2001;Ioannidis et al, 2001;Varas et al, 2003). The TOPflash plasmid was cotransfected together with an expression plasmid encoding a constitutively stabilized form of b-catenin (DN87bcat; Gat et al, 1998) and either pcDNA3-HOX11, pcDNA3-HOX11 H3d, pcDNA3-HOX11 Lys55Gln or the empty pcDNA3 vector.…”