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*
Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands;
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland; Departments of
Immunology and
§
Virology, University Hospital, Utrecht, The Netherlands; and
¶
Unité de Biologie Moléculaire du Gène, Institut Pasteur, Paris, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The murine thymus is seeded around embryonic days 10 to 11 (E10–11)3 by pluripotent progenitor cells that give rise to a wave of thymocytes and mature T cells, most of which have left the thymus 2 to 3 wk after birth (7). The fetal thymus increases exponentially in size from E11 to birth and up to 2 to 3 wk of age. To account for this, it has been shown that the majority of fetal thymocytes, regardless of phenotype, are cycling (7). In contrast, adult thymocyte numbers are kept at a relatively constant level over a period of time (from 4 wk to 3 mo of age) by homeostatic mechanisms. During adult life there is a continuous influx of small numbers of bone marrow-derived precursor cells sustaining continuous thymopoiesis (8), and a constant exit of mature CD4+ or CD8+ single positive (SP) T cells to the peripheral lymphoid organs.
The majority of thymocytes (
97%) express the T cell-specific
surface molecules (or coreceptors) CD4 and/or CD8. The initial
processes of differentiation, however, take place within the
CD4-8- double-negative (DN) compartment,
which can be divided into several subpopulations based on the
differential expression of CD44 and CD25 (1). Four major subsets
representing successive developmental stages can be distinguished: DN1
(CD44+CD25-), DN2
(CD44+CD25+), DN3
(CD44-CD25+), and DN4
(CD44-CD25-) (1, 9, 10). The most mature
subpopulation, DN4, rapidly differentiates through an intermediate
CD4-8+, immature (TCRlow) single
positive (ISP) stage (reviewed in 11 to the
CD4+8+ double positive (DP) stage.
Subsequently, most of these DP cells die due to either negative
selection or failure to be positively selected. A small number are
positively selected and mature to SP thymocytes (reviewed in 12 .
During differentiation along this pathway, the various TCR
genes are rearranged and expressed: the genes for the ß-, 
-, and
-chains early, at the DN2 to DN3 stages of development, and those of
the 
-chain later at the DP stage (13). The signals responsible for
initiating and driving this developmental pathway are still largely
unknown. However, at two specific points during thymocyte development,
DN subsets have been shown to contain a high proportion of cycling
cells (14, 15, 16). The first is in the DN2 subset and may correspond to
cells receiving survival and/or expansion signals through IL-7/IL-7R or
stem cell factor/c-kit receptor (CD117) interactions
(17, 18, 19, 20, 21). The second wave of expansion occurs after successful
rearrangement of the TCR ß-chain at the DN4 stage and is thought to
be mediated by signals through the pre-TCR complex (12). This complex,
consisting of a functional TCR ß-chain, the pT molecule (22), and
the CD3 chains, is expressed on immature thymocytes from DN3 through
DN4, ISP to the DP stage (23, 24), where it is replaced by a mature TCR
complex, containing a functional -chain instead of pT.
The ordered expression of all important genes in these differentiating cells is thought to be controlled through transcriptional regulation (25). The T cell-specific transcription factor, Tcf-1, is one factor implicated in this process. Tcf-1 is a T cell-specific DNA-binding nuclear protein that has been cloned and studied in our laboratory (26, 27). The DNA binding domain of Tcf-1 is a so-called HMG box, shared by many members of a recently identified gene family (28). Several members of this family have been shown to be involved in developmental processes in mammals (29, 30, 31, 32, 33). Although Tcf-1 expression is widely distributed in the embryo (34), its expression is confined to immature and mature T cells after birth. It is expressed in all thymocyte subpopulations, including the earliest, DN1, and represents the first definitive T-lineage marker (35, 36). Mice lacking a functional Tcf-1 gene develop normally, but their thymi start to age prematurely as a partial blockade in adult T cell development becomes gradually apparent after birth. This blockade occurs at the ISP stage when small, noncycling cells accumulate and the subsequent population of DP cells decreases dramatically in size, resulting in reduced numbers of total thymocytes. Although the thymus appears relatively normal until birth, fetal progenitors from various sources were found to be unable to develop properly upon transfer into normal fetal thymic organ cultures (FTOC) or adult thymi. The results show that Tcf-1-/- progenitors do not differentiate in normal numbers, probably because they fail to expand properly.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice were kept at the transgenic mouse facility of the central laboratory for experimental animals, University of Utrecht (Utrecht, The Netherlands). C57BL/6 (Charles River, Iffa Credo, France) and C57BL/6.Ly-5.1 (Ly-5.1; The Jackson Laboratory, Bar Harbor, ME) mice were purchased. Tcf-1 (exon VII)-deficient mice have been previously described (35) and were backcrossed to C57BL/6 mice for two to four generations. Because differences between Tcf-1+/- and Tcf-1+/+ mice were never observed, we have used both heterozygote and wild-type mice as controls in our experiments. Rag-1-/- mice were provided by Dr. A. Kruisbeek (Amsterdam, The Netherlands). For timed pregnancies, the day of vaginal plug was counted as day 0.5.
mAbs and flow cytometry
CD4-PE, TCRß-PE, TCR-PE, CD44-PE, CD62L-FITC
(Mel-14), and CD3-FITC were purchased from PharMingen (San Diego, CA).
CD4 (129-19), CD8 (53/6.7) (37), TCRß (H57-597) (38), CD25 (PC61),
CD24 (M1/69), B220 (RA3-6B2), Mac-1 (M1/70.15), Gr-1 (RB6-8C5), and
Ly-5.1 (A20) specific hybridomas were grown, and supernatant was
collected and purified. Abs were FITC conjugated or biotinylated
according to standard procedures. For flow cytometry, cell suspensions
were incubated with respective Abs, washed in PBS/FCS/sodium
azide, and subsequently analyzed on a FACScan (Becton Dickinson,
Palo Alto, CA). When triple-negative thymocyte populations were
examined, FITC-conjugated Abs specific for CD4, CD8, CD3, B220, Mac-1,
and Gr-1 were added, and negative cells were analyzed with CD44-PE and
CD25-Bio, followed by streptavidin-PerCP (Becton
Dickinson).
FACS sorting and DNA analysis
Individual thymi from normal or
Tcf-1-/- mice were stained for four-color
fluorescence with the following Abs: a mixture of FITC conjugates as
described above to eliminate
CD4+8+3+ß++
mature T cells, B cells granulocytes, and macrophages; CD44-PE;
CD25-Red613 (Life Technologies, Grand Island, NY); and CD24-biotin
followed by streptavidin-allophycocyanin (Molecular
Probes, Leiden, The Netherlands). FACS sorting was performed using a
FACStar+ (Becton Dickinson) by gating first on
FITC- CD24+ cells (immature
CD4-CD8-CD3-) and then for the
four populations defined by CD44 and CD25 expression. Fifty thousand
cells of each population were sorted from both normal and
Tcf-1-/- thymi. Propidium iodide in Nonidet
P-40 detergent was added to each sample, and DNA analysis was performed
as previously described (35) on a FACScan using the doublet
discrimination module. Control populations were total thymus and lymph
node.
Irradiation chimeras
Ly-5.1 mice were lethally irradiated (9.5 Gy), and within 24 h bone marrow cells (Ly-5.2) were injected i.v. as a cell suspension. All uninjected and 20 to 40% of injected mice died after 12 to 18 days. Host-derived cells were distinguished by staining with an Ly-5.1-specific Ab (A20). Donor cells always contributed >90% of the myeloid cells in the blood after 3 wk.
Fetal thymic organ cultures
Thymic lobes were dissected from E14.5 or E15.5 Ly5.1 embryos and irradiated (30 Gy). Individual lobes were cultured for 48 h in hanging drop cultures (Terasaki plates) together with aorta-gonad-mesonephros (AGM) cells (E11.5, one embryo equivalent per lobe) or fetal liver cells (E14.5, 2 x 104/lobe). Subsequently, the lobes were transferred to floating filters (0.8 µm pore size; Nuclepore polycarbonate, Costar, Cambridge, MA) in supplemented medium (Opti-MEM, Life Technologies) for 14 days. Lobes were teased apart individually and stained with mAbs. Only cells negative for Ly-5.1 were analyzed.
Intrathymic injections
Ly-5.1 mice (2–4 mo old) were sublethally irradiated (7.5 Gy) and anesthetized. The thorax was opened, and fetal cell suspensions were injected into the thymus (4 x 104 to 1 x 105 cells/10 µl). The thorax was closed immediately, and thymocyte subpopulations were analyzed 3 wk later by flow cytometry.
Stimulation assays
Spleen cells were isolated, counted, and stimulated in 96-well plates (4 x 104, 2 x 104, and 1 x 104/well) with Con A (2.5 µg/ml). For stimulation with alloantigen, irradiated spleen cells (1 x 106/well) were added to the responder cells (6 x 105, 2 x 105, and 6 x 104/well). After 3 days, [3H]thymidine (1 µCi/well) was added, and cells were harvested 18 h later. For cytotoxicity assays, 1 x 106/ml spleen cells were stimulated with 5 x 106/ml stimulator cells (CBA) in 24-well plates. After 6 days, cells were harvested and counted, and cytotoxic activity was tested against 51Cr-labeled Con A blasts (C57BL/6, H-2b and CBA, H-2k) in a 4-h assay according to standard procedures.
Virus immunization
BALB/c mice, Tcf-1+/-, and Tcf-1-/- mice were bled (preimmune sera) and immunized with 1000 plaque-forming units avirulent Semliki Forest virus (SFV) (39) s.c.. Two weeks later, blood was collected again, and titers of virus-neutralizing Abs were determined by a virus neutralization assay (40). Titers of SFV-specific Abs of various subclasses were determined by ELISA (41).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have previously reported (35) that thymi of 2-mo-old Tcf-1
(exon VII)-deficient mice are very small compared with thymi of
age-matched normal mice and have a partial blockade in T cell
development at the ISP stage. However, the differences between
Tcf-1-/- and normal control mice
(Tcf-1+/- or Tcf-1+/+,
phenotypic differences between heterozygote or wild-type mice were
never observed) were less apparent when the mice were only 2 to 3 wk
old. This observation raised the question of how thymopoiesis was
affected at different ages. To investigate this, thymi from
Tcf-1-/- embryos and mice of different ages
were analyzed in more detail. The results show that the thymic
phenotype, as defined by CD4 and CD8 expression, was similar in normal
and Tcf-1-/- E18.5 embryos (Fig. 1
). However, total numbers of thymocytes
were about fourfold lower, in Tcf-1-deficient E18.5 embryos compared
with controls (Fig. 1). This difference in total number of thymocytes
was apparent as early as E15.5 (0.14 x 106 for
control vs 0.095 x 106 for Tcf-1-/-
thymus) and became greater with increasing age (Fig. 1). By day 10
after birth, there were changes in the distribution of CD4 and CD8
expression, most notably a decrease in the percentage of DP cells (Fig. 1). These effects became even more pronounced with age, such that 4- to
8-mo-old mice typically contain around 1 x 106
thymocytes and are completely devoid of DP cells, indicating a total
lack of ongoing differentiation. Immature DN cells were still present,
as were a small number of mature SP (TCR+) cells that
probably represent the remnants of differentiation occurring at a
younger age or may have re-entered the thymus from the periphery.
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In Tcf-1-/- mice DP thymocytes fail to
develop from ISP thymocytes, which, unlike their counterparts in normal
thymi, are not in cycle (35). As a consequence, there is a relative
accumulation of ISPs in thymi of 1- to 2-mo-old mice, although absolute
numbers are not very different from those in control mice (Fig. 1
). The
total disappearance of ISPs in Tcf-1-/- mice
by 6 mo after birth suggests that an even earlier block in T cell
development may be present. Therefore, the DN compartment in young and
old thymi was analyzed in more detail using the CD44 and CD25 markers
that define the four subsets described above (Fig. 2). The earliest precursor population,
DN1 (CD44+CD25-), was present in all
Tcf-1-/- thymi analyzed. The majority of DN1
cells also expressed high levels of CD117 and CD24 (data not shown),
confirming that these cells are true T cell progenitors. However, the
next subpopulation, DN2 (CD44+25+), was missing
from all Tcf-1-/- thymi, even in mice of only
1 mo of age. DN3 (CD44-CD25+) thymocytes were
present in Tcf-1-/- mice, albeit at reduced
frequencies compared with normal thymi. In some thymi (10–20%) of
6-mo-old mice, the subset DN3 was completely absent. The most mature DN
subpopulation, DN4 (CD44-25-), was still
present at 1 mo of age but was missing at 6 mo of age (Fig. 2).
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). By contrast, in the absence of Tcf-1
none of the DN subsets isolated had any significant proportion of cells
in cycle. DN2 cells from Tcf-1-/- mice could
not even be analyzed because they were completely absent (Fig. 2), and
only 3% of DN4 cells from Tcf-1-/- mice were
in G2/S/M phase compared with 39% in the same population isolated from
normal mice (Fig. 3).
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Lack of Tcf-1 affects lymphocytes and not stromal cells
The inability of Tcf-1-/- T cell
precursors to differentiate into mature T cells could be due to an
inherent defect in the hemopoietic precursors themselves or to defects
in the thymic stroma or microenvironment. Therefore, Tcf-1-deficient
bone marrow cells (Ly-5.2) were injected i.v. into lethally irradiated
normal (C57BL/6.Ly-5.1) hosts, and the thymi of these chimeras were
analyzed 2 mo after reconstitution. While control bone marrow fully
reconstituted host thymi with both immature and mature
TCRß-expressing T cells, thymi reconstituted with Tcf-1-deficient
bone marrow had 100-fold fewer cells, 90% of which were of host origin
(Fig. 4, A and B).
Similar results were obtained when Tcf-1-/-
fetal liver cells were used as donor cells (data not shown). Reciprocal
experiments in which normal bone marrow was injected into
Tcf-1-/- hosts demonstrated that
Tcf-1-deficient thymi are able to support normal T cell development
(data not shown), as reconstitution occurred normally. Taken together,
these experiments demonstrate that the
Tcf-1-/- stromal environment is capable of
supporting thymocyte differentiation and that the phenotype observed in
Tcf-1-/- mice is due to a defect in the
hemopoietic compartment.
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As the expansion of Tcf-1-/- thymocytes
appeared to be affected in adult mice more than in mutant embryos, the
differentiative potential of fetal progenitors was investigated in
transfer experiments. E18.5 fetal bone marrow cells or E12.5 fetal
liver cells from Tcf-1 deficient or normal embryos were injected
intrathymically into sublethally (7.5 Gy) irradiated Ly-5.1 hosts.
While progenitors from both organs of normal embryos successfully
reconstituted the thymus 3 wk after transfer, no thymocytes of donor
origin were detected in mice reconstituted with Tcf-1-deficient
precursors (Fig. 4, C–F).
Failure of the Tcf-1-/- fetal progenitors to
develop could be due to incompatibility with the adult
microenvironment. Therefore, fetal liver (E14.5) progenitor cells from
Tcf-1-/- embryos were allowed to differentiate
in a normal fetal environment in FTOC. Also under these conditions
Tcf-1-/- cells were unable to differentiate
into DP or SP thymocytes (Fig. 5). As the
first progenitors that colonize the embryonic thymus are derived from
the AGM region around E10–11, we investigated whether cells from the
AGM of Tcf-1-/- embryos could give rise to T
cells after transfer to a normal fetal environment in FTOC. It was
observed that Tcf-1-/- cells did not
differentiate into significant numbers of
CD4+CD8+DP cells, while control AGM did (Fig. 5). Some T cells did arise in the lobes reconstituted with
Tcf-1-/- AGM cells, confirming that the lobes
were indeed seeded by progenitor cells. It has been reported that the
development of T cells is only moderately dependent on the
presence of Tcf-1 (44). Together, these data indicate that although the
fetal Tcf-1-/- thymus appears to contain
reduced numbers of normal thymocytes, the observed defect in
differentiation of Tcf-1-/- cells is present
in the earliest precursor cells (AGM) of the mutant embryo.
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Despite the absence of Tcf-1, mature T cells accumulate in the
peripheral lymphoid organs. Peripheral T lymphocyte numbers are about
two- to threefold lower than those in control mice, but their level
remains stable with increasing age (35). When analyzed phenotypically,
Tcf-1-deficient mature T cells were shown to express markers typical of
cells with an activated phenotype. Naive T cells recently produced by
the thymus normally do not express CD44, while peripherally expanded
activated T cells do (45). Analysis of lymph node cells of
Tcf-1-/- mice revealed an increase in the
proportion of CD44+ cells, most pronounced in the
CD8+ subset (Fig. 6). This
effect became more obvious with increasing age (data not shown),
indicating a lack of CD8+ T cell production by the thymus.
Correspondingly, a higher proportion of CD4+ T cells in
Tcf-1-/- mice lack the surface marker CD62L
(Mel-14; Fig. 6) that is normally expressed at high levels on most
mature T cells and is only down-regulated on activated cells.
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A)
and alloantigen (Fig. 7B) to a level equivalent to that in
normal splenocytes. In addition, the cytolytic activity of
Tcf-1-/- alloantigen-specific CTLs at fixed
E:T cell ratios was the same as that of normal or heterozygote mice
(Fig. 7C). Finally, Th cell function in
Tcf-1-/- mice was normal, as determined in
vivo by quantitation of circulating IgG Abs after infection with SFV.
Tcf-1-/- mice produced high titers of virus
neutralizing Abs, comparable to or higher than those obtained in
heterozygous and BALB/c mice (Table I).
Taken together, these results show that although the numbers of
peripheral T cells in Tcf-1-/- mice are low,
their responsiveness is normal.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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During thymocyte development there are two stages at which extensive
proliferation is observed. The first occurs just before rearrangement
of the TCR ß-chain at the DN2 (CD44+25+)
stage, while the second occurs after surface expression of the pre-TCR
(post-DN3) and requires a functional TCR ß-chain. This latter
expansion phase involves the DN4 (CD44-25-)
and ISP subsets that rapidly transit through to the DP stage, where
TCR is rearranged and expressed. From the experiments in this study
it can be concluded that Tcf-1-/- thymocytes
have an impaired capability to expand at both these stages.
The second blockade in differentiation cannot easily be explained by
the absence of pre-TCR components, as pT, CD3
, and TCRß were
all expressed at relatively normal levels (data not shown). The first
observed block in Tcf-1-/- thymocyte
differentiation occurs just before or at the time at which TCRß gene
rearrangement commences (DN2). To our knowledge, this is the earliest
block in T cell differentiation by mutation of a T cell-specific gene.
The only other examples of such an early block are found in mice
transgenic for the human CD3 gene (46), which is copy
number dependent and may be due to sequestration of downstream
signaling molecules rather than to a direct effect of CD3, and in mice
that are unable to signal via both the IL-7/IL-7R pathway and the
c-kit/stem cell factor pathway (20). Earlier blocks in
lymphocyte development have been described (47, 48), but these
mutations result in the absence of all lymphocytes (T, B, and NK
cells).
Although the blockades in differentiation of postnatal and adult thymocytes are very clear, a similar lack of differentiation was not very obvious in thymi of the developing Tcf-1(VII)-/- embryos or when the Tcf-1(VII)-/- thymi were cultured in FTOC (49). However, after transfer to a normal environment (in FTOC or after intrathymic injection), Tcf-1-/- progenitors do not differentiate as their control counterparts. The reason for this observation is unclear. One possibility is that after transfer, reconstitution depends on the expansion of fewer progenitors than when seeding occurs under physiologic conditions. A relative inability to expand of the Tcf-1-/- progenitors could become more obvious under such restrictive conditions. A comparable situation was recently observed in Tcf-4 mutant mice, in which colonic epithelium is present around birth but fails to persist due to a lack of stem cell activity (V. Korinek, N. Barker, P.M., E. van Donselaar, G. Huls, P. J. Peters, and H.C.C., unpublished observations).
From the described experiments it seems clear that the expansion of Tcf-1-/- thymocytes is affected. At the DN4/ISP stage, this appears to be due to a lack of cycling cells. At the DN2 stage it is not clear whether cell cycle progression or cell survival (or both) is impaired. It was recently reported that thymus-specific inactivation of the GTPase, Rho, affected development of thymocytes in a very similar way to that reported here (50), as both the CD25+ (DN2/3) as well as the DN4 subpopulations were affected. It was demonstrated that, on the one hand, while Rho is required for survival but not expansion of the DN2/3 thymocytes, it is required for cell cycle progression but not survival of the later DN4 cells, on the other hand (51).
Due to the lack of adult T lymphopoiesis in the absence of Tcf-1, the peripheral T cell compartment in adult Tcf-1-/- mice is derived mostly from fetal thymocytes. The number of T lymphocytes in lymphoid organs and blood of Tcf-1-/- mice is lower than that in normal mice, and the phenotype of these cells is generally that of activated T cells (CD8+CD44+ and CD4+Mel-14-). This is similar to the phenotype observed in the periphery of thymectomized mice (52), where the peripheral T cell pool appears to be maintained by peripheral expansion (45). Functionally, the peripheral T cells appear indistinguishable from normal T cells, as while expansion during maturation of thymocytes appears to be limited, expansion of mature Tcf-1-/- T lymphocytes in response to mitogenic/antigenic stimuli is unaffected. This suggests that the molecular processes required for proliferation of thymocytes and T lymphocytes are distinct, as previously reported (53).
Recently, it has been shown that Tcf-1 (and Lef-1) can associate with ß-catenin (54, 55, 56). ß-Catenin associates with the cadherin family of cellular adhesion molecules and provides the link between gap junctions and the actin cytoskeleton. A role for E-cadherin in thymus development has been suggested (57). Anti-E-cadherin Abs inhibit thymic reaggregation and interfere with the seeding and/or maturation of fetal liver derived progenitors in deoxyguanosine-treated thymic lobes. ß-Catenin is also a key component of the Wnt/Wingless signaling pathway. In this function, ß-catenin is present in the cytoplasm, usually in complex with the tumor suppressor protein adenomatous polyposis coli (58). Wnt/ß-catenin/Tcf signaling occurs in systems as diverse as Drosophila segment polarity, Xenopus axis formation, and colon tumorigenesis (54, 55, 56, 58, 59, 60, 61). Molecularly, the function of ß-catenin in cellular adhesion resides in a different part of the protein than its function in Wnt signaling. In Drosophila it has been demonstrated that although cadherins associate with armadillo (the Drosophila homologue of ß-catenin) from the same pool as that used in the wingless signaling pathway, wingless does not specify cell fate by modulating cell-cell adhesion (62). The specific defect in differentiation of thymocytes suggests a direct role of Tcf/Lef transcription factors downstream of ß-catenin in a signaling cascade crucial for DN thymocyte expansion. Whether Tcf-1 exerts this role in transduction of signals from a Wnt-like factor or in cellular adhesion events (or both) remains uncertain at the moment. Nevertheless, the present results raise the possibility that Wnt-like factors are required for normal thymopoiesis.
Note added in proof. Unpublished observations have been published: Korinek, V., N. Barker, E. van Donselaar, G. Huls, P. J. Peters, and H. Clevers. 1998. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat. Genet. 19:379.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Marco Schilham, Laboratory for Immunology, P3-P, Department of Pediatrics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail:
3 Abbreviations used in this paper: E, embryonic day; SP, single positive; DN, double negative; ISP, immature single positive; DP, double positive; FTOC, fetal thymic organ culture; PE, phycoerythrin; AGM, aorta-gonad-mesonephros; SFV, Semliki Forest virus.
Received for publication March 17, 1998. Accepted for publication June 16, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and ß block thymocyte development at different stages. Nature 360:225.[Medline]
gene rearrangement and T early (TEA) expression in immature ß lineage thymocytes: implications for ß/ lineage commitment. Immunity 4:37.[Medline]
chain. Proc. Natl. Acad. Sci. USA 92:377.ß or T cell receptors. J. Immunol. 150:447.[Abstract]
gene in development of ß but not cells. Nature 375:795.[Medline]
and the T cell receptor enhancers. J. Exp. Med. 173:1133.ß T cell receptors. J. Immunol. 142:2736.[Abstract]
+ cells and liver CD4+ NK1+ T cell receptor ß+ cells in T cell factor-1-deficient mice. Eur. J. Immunol. 26:351.[Medline]
gene expression by the transcription factors LEF-1 and TCF-1. Immunity 8:11.[Medline]
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 M. Xu, Q. Yu, R. Subrahmanyam, M. J. Difilippantonio, T. Ried, and J. M. Sen {beta}-Catenin Expression Results in p53-Independent DNA Damage and Oncogene-Induced Senescence in Prelymphomagenic Thymocytes In Vivo Mol. Cell. Biol., March 1, 2008; 28(5): 1713 - 1723. [Abstract] [Full Text] [PDF]
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U. Koch, A. Wilson, M. Cobas, R. Kemler, H. R. MacDonald, and F. Radtke Simultaneous loss of - and {gamma}-catenin does not perturb hematopoiesis or lymphopoiesis Blood, January 1, 2008; 111(1): 160 - 164. [Abstract] [Full Text] [PDF]
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G. Jeannet, M. Scheller, L. Scarpellino, S. Duboux, N. Gardiol, J. Back, F. Kuttler, I. Malanchi, W. Birchmeier, A. Leutz, et al. Long-term, multilineage hematopoiesis occurs in the combined absence of -catenin and {gamma}-catenin Blood, January 1, 2008; 111(1): 142 - 149. [Abstract] [Full Text] [PDF]
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 H. Liang, A. H. Coles, Z. Zhu, J. Zayas, R. Jurecic, J. Kang, and S. N. Jones Noncanonical Wnt signaling promotes apoptosis in thymocyte development J. Exp. Med., December 24, 2007; 204(13): 3077 - 3084. [Abstract] [Full Text] [PDF]
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Z. Guo, M. Dose, D. Kovalovsky, R. Chang, J. O'Neil, A. T. Look, H. von Boehmer, K. Khazaie, and F. Gounari {beta}-Catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation Blood, June 15, 2007; 109(12): 5463 - 5472. [Abstract] [Full Text] [PDF]
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 H. J. Melichar, K. Narayan, S. D. Der, Y. Hiraoka, N. Gardiol, G. Jeannet, W. Held, C. A. Chambers, and J. Kang Regulation of {gamma}{delta} Versus {alpha}{beta} T Lymphocyte Differentiation by the Transcription Factor SOX13 Science, January 12, 2007; 315(5809): 230 - 233. [Abstract] [Full Text] [PDF]
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 K. H. Choi, M. W. Park, S. Y. Lee, M.-Y. Jeon, M. Y. Kim, H. K. Lee, J. Yu, H.-J. Kim, K. Han, H. Lee, et al. Intracellular expression of the T-cell factor-1 RNA aptamer as an intramer. Mol. Cancer Ther., September 1, 2006; 5(9): 2428 - 2434. [Abstract] [Full Text] [PDF]
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Z. Huang, H. Xie, V. Ioannidis, W. Held, H. Clevers, M. S. Sadim, and Z. Sun Transcriptional Regulation of CD4 Gene Expression by T Cell Factor-1/beta-Catenin Pathway. J. Immunol., April 15, 2006; 176(8): 4880 - 4887. [Abstract] [Full Text] [PDF]
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 F. Weerkamp, M. R. M. Baert, B. A. E. Naber, E. E. L. Koster, E. F. E. de Haas, K. R. Atkuri, J. J. M. van Dongen, L. A. Herzenberg, and F. J. T. Staal Wnt signaling in the thymus is regulated by differential expression of intracellular signaling molecules PNAS, February 28, 2006; 103(9): 3322 - 3326. [Abstract] [Full Text] [PDF]
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T. Willinger, T. Freeman, M. Herbert, H. Hasegawa, A. J. McMichael, and M. F. C. Callan Human Naive CD8 T Cells Down-Regulate Expression of the WNT Pathway Transcription Factors Lymphoid Enhancer Binding Factor 1 and Transcription Factor 7 (T Cell Factor-1) following Antigen Encounter In Vitro and In Vivo J. Immunol., February 1, 2006; 176(3): 1439 - 1446. [Abstract] [Full Text] [PDF]
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H. Xie, Z. Huang, M. S. Sadim, and Z. Sun Stabilized {beta}-Catenin Extends Thymocyte Survival by Up-Regulating Bcl-xL J. Immunol., December 15, 2005; 175(12): 7981 - 7988. [Abstract] [Full Text] [PDF]
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D. Goux, J. D. Coudert, D. Maurice, L. Scarpellino, G. Jeannet, S. Piccolo, K. Weston, J. Huelsken, and W. Held Cooperating pre-T-cell receptor and TCF-1-dependent signals ensure thymocyte survival Blood, September 1, 2005; 106(5): 1726 - 1733. [Abstract] [Full Text] [PDF]
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R. Terra, I. Louis, R. Le Blanc, S. Ouellet, J. C. Zuniga-Pflucker, and C. Perreault T-cell generation by lymph node resident progenitor cells Blood, July 1, 2005; 106(1): 193 - 200. [Abstract] [Full Text] [PDF]
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E. A. Ranheim, H. C. K. Kwan, T. Reya, Y.-K. Wang, I. L. Weissman, and U. Francke Frizzled 9 knock-out mice have abnormal B-cell development Blood, March 15, 2005; 105(6): 2487 - 2494. [Abstract] [Full Text] [PDF]
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 R. van Amerongen, M. Nawijn, J. Franca-Koh, J. Zevenhoven, H. van der Gulden, J. Jonkers, and A. Berns Frat is dispensable for canonical Wnt signaling in mammals Genes & Dev., February 15, 2005; 19(4): 425 - 430. [Abstract] [Full Text] [PDF]
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 D. N. Everly Jr., S. Kusano, and N. Raab-Traub Accumulation of Cytoplasmic {beta}-Catenin and Nuclear Glycogen Synthase Kinase 3{beta} in Epstein-Barr Virus-Infected Cells J. Virol., November 1, 2004; 78(21): 11648 - 11655. [Abstract] [Full Text] [PDF]
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S. Hoflinger, K. Kesavan, M. Fuxa, C. Hutter, B. Heavey, F. Radtke, and M. Busslinger Analysis of Notch1 Function by In Vitro T Cell Differentiation of Pax5 Mutant Lymphoid Progenitors J. Immunol., September 15, 2004; 173(6): 3935 - 3944. [Abstract] [Full Text] [PDF]
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 J. Tournoy, X. Bossuyt, A. Snellinx, M. Regent, M. Garmyn, L. Serneels, P. Saftig, K. Craessaerts, B. De Strooper, and D. Hartmann Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice Hum. Mol. Genet., July 1, 2004; 13(13): 1321 - 1331. [Abstract] [Full Text] [PDF]
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P. W. B. Derksen, E. Tjin, H. P. Meijer, M. D. Klok, H. D. Mac Gillavry, M. H. J. van Oers, H. M. Lokhorst, A. C. Bloem, H. Clevers, R. Nusse, et al. Illegitimate WNT signaling promotes proliferation of multiple myeloma cells PNAS, April 20, 2004; 101(16): 6122 - 6127. [Abstract] [Full Text] [PDF]
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P. L. Coletta, A. M. Muller, E. A. Jones, B. Muhl, S. Holwell, D. Clarke, J. L. Meade, G. P. Cook, G. Hawcroft, F. Ponchel, et al. Lymphodepletion in the ApcMin/+ mouse model of intestinal tumorigenesis Blood, February 1, 2004; 103(3): 1050 - 1058. [Abstract] [Full Text] [PDF]
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M. Cobas, A. Wilson, B. Ernst, S. J.C. Mancini, H. R. MacDonald, R. Kemler, and F. Radtke {beta}-Catenin Is Dispensable for Hematopoiesis and Lymphopoiesis J. Exp. Med., January 20, 2004; 199(2): 221 - 229. [Abstract] [Full Text] [PDF]
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F. J. T. Staal, F. Weerkamp, M. R. M. Baert, C. M. M. van den Burg, M. van Noort, E. F. E. de Haas, and J. J. M. van Dongen Wnt Target Genes Identified by DNA Microarrays in Immature CD34+ Thymocytes Regulate Proliferation and Cell Adhesion J. Immunol., January 15, 2004; 172(2): 1099 - 1108. [Abstract] [Full Text] [PDF]
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C. K. Kaufman, P. Zhou, H. A. Pasolli, M. Rendl, D. Bolotin, K.-C. Lim, X. Dai, M.-L. Alegre, and E. Fuchs GATA-3: an unexpected regulator of cell lineage determination in skin Genes & Dev., September 1, 2003; 17(17): 2108 - 2122. [Abstract] [Full Text] [PDF]
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 D. M. Dorfman, H. A. Greisman, and A. Shahsafaei Loss of Expression of the WNT/{beta}-Catenin-Signaling Pathway Transcription Factors Lymphoid Enhancer Factor-1 (LEF-1) and T Cell Factor-1 (TCF-1) in a Subset of Peripheral T Cell Lymphomas Am. J. Pathol., May 1, 2003; 162(5): 1539 - 1544. [Abstract] [Full Text] [PDF]
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I. Ferrero, W. Held, A. Wilson, F. Tacchini-Cottier, F. Radtke, and H. R. MacDonald Mouse CD11c+ B220+ Gr1+ plasmacytoid dendritic cells develop independently of the T-cell lineage Blood, September 26, 2002; 100(8): 2852 - 2857. [Abstract] [Full Text] [PDF]
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W. C. Kieper and S. C. Jameson Homeostatic expansion and phenotypic conversion of naive T cells in response to self peptide/MHC ligands PNAS, November 9, 1999; 96(23): 13306 - 13311. [Abstract] [Full Text] [PDF]
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J. Roose, G. Huls, M. v. Beest, P. Moerer, K. v. d. Horn, R. Goldschmeding, T. Logtenberg, and H. Clevers Synergy Between Tumor Suppressor APC and the -Catenin-Tcf4 Target Tcf1 Science, September 17, 1999; 285(5435): 1923 - 1926. [Abstract] [Full Text]
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 C. MURRE Role of Helix-Loop-Helix Proteins in Lymphocyte Development Cold Spring Harb Symp Quant Biol, January 1, 1999; 64(0): 39 - 44. [Abstract] [PDF]
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