Wnt signaling is required for thymocyte development and activates Tcf-1 mediated transcription.
ABSTRACT T cell factor / lymphocyte enhancer factor (Tcf/Lef) transcription factors complex with the transcriptional co-activator beta-catenin to transduce Wnt signals in a variety of developmental systems. The prototypic family member Tcf-1 is highly expressed in T lineage cells. Tcf1-/- mice are defective in cell cycling of early thymocyte stages. Here, we show that the interaction of beta-catenin with Tcf-1 is required for full thymocyte development. This interaction may be established by signals mediated by Wnt1 and Wnt4, leading to increased Tcf-dependent transcriptional activity in thymocytes, as demonstrated in Tcf-LacZ reporter mice. Transduction of fetal thymocytes with Wnt1 and Wnt4 results in increased survival in an in vitro cell culture system. Retroviral expression of soluble Wnt receptor mutants that block Wnt signaling inhibits thymocyte development. These results imply an important role for the Wnt cascade in thymocyte development.
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- "OP9-DL1 stromal cells were found to express several Wnt genes, including Wnt4 and Wnt5A, and to a lesser extent, Wnt5B and Wnt10B (Fig. 5B). Of these, Wnt4 has previously been reported to have a role in thymopoiesis (Staal et al., 2001; Mulroy et al., 2002). OP9-Ctrl cells showed a similar pattern of Wnt gene expression (data not shown). "
ABSTRACT: Functional decline of the hematopoietic system occurs during aging and contributes to clinical consequences, including reduced competence of adaptive immunity and increased incidence of myeloid diseases. This has been linked to aging of the hematopoietic stem cell (HSC) compartment and has implications for clinical hematopoietic cell transplantation as prolonged periods of T-cell deficiency follow transplantation of adult mobilized peripheral blood (PB), the primary transplant source. Here, we examined the gene expression profiles of young and aged HSCs from human cord blood and adult mobilized PB, respectively, and found that Wnt signaling genes are differentially expressed between young and aged human HSCs, with less activation of Wnt signaling in aged HSCs. Utilizing the OP9-DL1 in vitro co-culture system to promote T-cell development under stable Notch signaling conditions, we found that Wnt signaling activity is important for T-lineage differentiation. Examination of Wnt signaling components and target gene activation in young and aged human HSCs during T-lineage differentiation revealed an association between reduced Wnt signal transduction, increasing age, and impaired or delayed T-cell differentiation. This defect in Wnt signal activation of aged HSCs appeared to occur in the early T-progenitor cell subset derived during in vitro T-lineage differentiation. Our results reveal that reduced Wnt signaling activity may play a role in the age-related intrinsic defects of aged HSCs and early hematopoietic progenitors and suggest that manipulation of this pathway could contribute to the end goal of improving T-cell generation and immune reconstitution following clinical transplantation.Aging cell 05/2014; 13(4). DOI:10.1111/acel.12229 · 5.94 Impact Factor
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- "All minimal promoters in previously generated Wnt/b-catenin signaling reporters were derived from the promoters of natural genes, such as heat shock protein, c-fos, thymidine kinase, and siamois (Riese et al., 1997; DasGupta and Fuchs, 1999; Staal et al., 2001; Dorsky et al., 2002; Geng et al., 2003; Maretto et al., 2003; Mohamed et al., 2004; Nakaya et al., 2005; Denayer et al., 2006; Moro et al., 2012). They not only contained TATA but also sequences derived from each gene promoter, which may be affected by non-specific signals (Robertson et al., 1995; Barolo, 2006). "
ABSTRACT: Evolutionarily conserved Tcf/Lef transcription factors (Lef1, Tcf7, Tcf7l1, and Tcf7l2) mediate gene expression regulated by Wnt/β-catenin signaling, which has multiple roles in early embryogenesis, organogenesis, adult tissue homeostasis, and tissue regeneration. However, the spatiotemporal dynamics of Tcf/Lef activity during these events remain poorly understood. We generated stable transgenic zebrafish lines carrying a new Wnt/β-catenin signaling reporter, Tcf/Lef-miniP:dGFP. The reporter revealed the transcriptional activities of four Tcf/Lef members controlled by Wnt/β-catenin signaling, which were expressed in known Wnt/β-catenin signaling-active sites during embryogenesis, organ development and growth, and tissue regeneration. We used the transgenic lines to demonstrate the contribution of Tcf/Lef-mediated Wnt/β-catenin signaling to the development of the anterior lateral line, dorsal and secondary posterior lateral lines, and gill filaments. Thus, these reporter lines are highly useful tools for studying Tcf/Lef-mediated Wnt/β-catenin signaling-dependent processes.Developmental Biology 07/2012; 370(1):71-85. DOI:10.1016/j.ydbio.2012.07.016 · 3.64 Impact Factor
Senescence, 02/2012; , ISBN: 978-953-51-0144-4
- "The canonical pathway has been shown to have an important role in thymocyte development regulating survival and differentiation (Ioannidis et al. 2001; Staal 2001; Pongracz et al. 2003; Xu et al. 2003). In a thymic epithelial cell study, transgenic expression of cyclin-D1, one of the principal target genes of Wnt signalling, has lead to the expansion of the entire epithelial compartment (Klug et al. 2000) suggesting that canonical Wnt signalling is involved in thymic epithelial cell proliferation, strengthening the argument, that thymic epithelial development is regulated by Wnt-s. "