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First published online January 24, 2007
doi: 10.1242/10.1242/jcs.03363

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Wnt signalling: variety at the core

Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK

View larger version (23K): [in this window] [in a new window]   Fig. 1. Wnt/-catenin signalling as a tale of four multiprotein complexes. Two snapshots of the dynamic processes in the Wnt/-catenin signal transduction cascade that involve multiprotein complexes. (A) In the presence of extracellular Wnt signalling, Wnt receptor complexes assemble in the cell membrane (Complex 1); as a consequence, -catenin is able to form transcription activation complexes with TCF/LEFs in the nucleus (Complex 3). (B) In the absence of extracellular Wnt signalling, -catenin destruction complexes assemble (Complex 2), leaving TCF/LEF to form transcription-repressing complexes with transcriptional co-repressors (Complex 4). A, Axin protein; , -catenin protein; TCF, TCF or LEF protein; W, extracellular Wnt signal. For further details, see main text, recent reviews (e.g. Cadigan and Liu, 2006; Willert and Jones, 2006) and the Wnt homepage (http://www.stanford.edu/~rnusse/wntwindow.html).

View larger version (31K): [in this window] [in a new window]   Fig. 2. The structural variety of vertebrate TCF/LEFs. Protein-coding exon structure is shown for a generic invertebrate Tcf gene and generic vertebrate Tcf-1, Lef-1, Tcf-3 and Tcf-4 genes or in HUGO nomenclature, TCF7, LEF1, TCF7L1 and TCF7L2, respectively (from top to bottom, with N-terminal exons on the left and C-terminal exons on the right). Note the four broad domains of TCF proteins: N-terminal domain, central domain, DNA-binding domain and C-terminal tail. Described protein-protein interaction domains and polypeptide motifs that are conserved between invertebrate and vertebrate TCF proteins are indicated between the invertebrate and the vertebrate TCFs. The N-terminal -catenin-binding domain (BCBD) is marked in green, the interaction domain with the groucho/TLE transcriptional co-repressors in red, the HMG DNA-binding domain in dark blue, the nuclear localisation signal (NLS) in turquoise, the CRARF motif in mid blue and the RKKKCIRY motive in pale blue. Note the central exon coloured yellow, which is an obligatory exon in invertebrate TCFs and in vertebrate TCF-3 and TCF-4, but an alternative exon in vertebrate TCF-1 and LEF-1. Described protein-protein interaction domains and polypeptide motives in certain Tcf genes that are conserved among vertebrates but apparently not with invertebrate Tcf genes are indicated below the vertebrate TCFs. They are the LVPQ and SxxSS motives in the central domain and the C-terminal domain described as a CtBP-binding domain (purple) present in alternatively spliced vertebrate TCF-4 isoforms, but always present in vertebrate TCF-3. The identified SUMOylation sites in LEF-1 (K25) and in TCF-4 (K297) are indicated in grey. Alternative translation initiation sites for TCF-1 and LEF-1 are indicated, which produce N-TCF isoforms lacking the -catenin-binding domain (BCBD). For further detail, see main text and recent molecular review (Arce et al., 2006).

View larger version (13K): [in this window] [in a new window]   Fig. 3. Diverse functions for Xenopus TCF/LEFs. Required roles for TCF/LEFs in early Xenopus development from fertilisation (left in figure) to gastrulation stages of development (right in figure). Maternal expression of Tcf genes is required for regulating dorsal axis induction, with TCF-3 expression being required for repressing transcription and TCF-1 expression being required for activating transcription. However, TCF-1 is also required in a repressing function and TCF-3 and TCF-4 function partially redundantly with TCF-1 in activating transcription of target genes of dorsal axis development (see Standley et al., 2006). Zygotic expression of Tcf/Lef genes is required for regulating mesoderm induction and subsequent mesoderm patterning, with TCF-3 required as a transcriptional repressor and TCF-1 required as a transcriptional activator for mesoderm induction and TCF-1 and LEF-1 required as transcriptional activators for mesoderm patterning (see Liu et al., 2005).

View larger version (32K): [in this window] [in a new window]   Fig. 4. TCF/LEF function in intestine and colorectal cancer. The stem cell population at the base of the crypt in the intestine produces a proliferating progenitor cell population that migrates up the side of the crypt. Upon reaching the crypt-villus junction, cells begin to differentiate and continue moving up the villus until mature cells are shed into the lumen at the tip of the villus. The levels of nuclear -catenin, and therefore active TCF/LEF, are highest at the base of the crypt in the stem cell and proliferating progenitor population. In this population it is proposed that full-length TCF-4 (activating, green) and NTCF-1 (repressing, red) are the main active TCF/LEFs. However, when mutated Wnt signalling leads to colorectal cancer, ectopic expression of full-length LEF-1 is readily detected. As a result the predominant TCF/LEF isoforms present in colorectal cancer are activating (green) as opposed to repressive (red) TCF/LEFs. The levels of nuclear -catenin in colorectal cancer are very high because Wnt signalling pathway mutations mean that -catenin cannot be degraded. Figure modified from Radtke and Clevers (Radtke and Clevers, 2005).

View larger version (42K): [in this window] [in a new window]   Fig. 5. TCF/LEF function in skin and hair. Structure and tissues of the mammalian hair follicle (A) and the differentiation pathways (black arrows) of multipotent stem cells in the skin (B). The stem cell niche (SC) resides in the bulge of the hair follicle and gives rise to the tissues of the epidermis of the skin (E), the sebaceous gland (SG), the outer-root sheath (ORS) the inner-root sheath (ORS) and the hair shaft (H). Larger rings in B represent cells, whereas the smaller rings within them represent their cell nuclei. The expression of TCF-3 and LEF-1 are indicated with the letter T or L, respectively, in the cell nuclei of cells. Note that LEF-1 is expressed in cells of the hair differentiation pathway, TCF-3 in the stem cells and the adjacent ORS, while the tissues of the skin (E and SG) are devoid of any TCF/LEF expression. The molecular activities of TCF-3 and LEF-1 are decisively different during hair and skin differentiation. Overexpression of full-length LEF-1 promotes hair differentiation (illustrated in B with green dotted arrow); whereas overexpression of full-length TCF-3 or constitutively repressing NTCF-3 prevents skin differentiation (E and SG, illustrated with red dotted inhibitory arrow) and promotes stem cell (SC) maintenance and differentiation into the adjacent ORS tissue (indicated with red dotted arrow). Overexpression of NLEF-1 interferes with hair differentiation by promoting trans-differentiation into cells that resemble those of the sebaceous gland (SG, indicated with red dotted arrow). TCF-3 therefore functions primarily as a repressor (indicated in red), while LEF-1 functions as an activator (indicated in green). Figure modified from Merrill et al. (Merrill et al., 2001).

View larger version (70K): [in this window] [in a new window]   Fig. 6. TCF/LEF function in the immune system. Stages of B-cell and T-cell development are illustrated in bone marrow and thymus, respectively. Large rings represent cells and the smaller rings within them represent their nuclei. Wnt signalling is thought to regulate cell proliferation and apoptosis during lymphocyte development. TCF-1 and LEF-1 expression is indicated with the letter T or L, respectively, in the cell nuclei of cells. Note that TCF-1 and LEF-1 are both expressed during T-cell development. Red stars indicate defects in lymphocyte development reported in Lef-1 knockout mice; red lightening indicates defects in lymphocyte development observed in Tcf-1 knockdown mice; and the red stop sign indicates the complete block of T-cell development observed in Tcf1/Lef1 double mutant mice. Note that in T-cell development, TCF-1 functions to some extent redundantly with LEF-1, because the double mutant phenotype is more severe than the single Tcf-1 knockout phenotype, yet also non-redundantly, because the single Tcf-1 knockout phenotype is more severe than the Lef-1 knockout phenotype. Stages of B-cell development: HSC, haematopoietic stem cells; MLP, multi-lineage precursors; CLP, common lymphoid precursors; ePB, early pre-B-cells; pPB, proliferating pro-B cells; lPB, late pre-B-cells; iBC, immature B cells; mBC, mature B cells. Stages of T-cell development: DN1-DN3, double-negative thymocytes stages one to three; ISP, immature single positive thymocytes (or double-negative thymocytes at stage four); DP, double-positive thymocites; SP, single-positive thymocyctes (see Staal and Clevers, 2005). Figure modified from Staal and Clevers (Staal and Clevers, 2005).