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WNT signalling and haematopoiesis: a WNT–WNT situation

Nature Reviews Immunology volume 5, pages 21–30 (2005)Cite this article

Key Points

  • WNT-mediated signalling involves the binding of WNT proteins to their receptor–co-receptor complexes, frizzled–LRP (low-density-lipoprotein-receptor-related protein), which leads (by several steps) to the accumulation of β-catenin and its translocation to the nucleus. In the nucleus, β-catenin forms a bipartite transcription-factor complex with T-cell factor (TCF) to activate target genes.

  • For haematopoietic stem cells (HSCs), the WNT-signalling pathway provides signals for self-renewal proliferation.

  • In the thymus, WNT signalling provides proliferative signals to double-negative thymocytes.

  • TCF1-deficient mice have severe defects in immature thymocyte development. LEF1 (lymphocyte-enhancer-binding factor 1) partially compensates for TCF1.

  • WNT-deficient mice have mild thymic phenotypes, probably because of molecular redundancy. Inhibition of WNT signalling by other means (for example, using soluble frizzled ectodomains) results in more pronounced inhibition of T-cell development.

  • WNT signals are also implicated in the survival of double-positive thymocytes and in the development of thymic epithelial cells.

  • Studies of β-catenin-deficient mice have generated conflicting results regarding thymic phenotype.

  • WNT proteins also provide proliferative signals to pro-B cells.

  • Dysregulated WNT signalling is implicated in various haematological malignancies.

Abstract

The evolutionarily conserved WNT-signalling pathway has pivotal roles during the development of many organ systems, and dysregulated WNT signalling is a key factor in the initiation of various tumours. Recent studies have implicated a role for WNT signal transduction at several stages of lymphocyte development and in the self-renewal of haematopoietic stem cells. Here, we outline new insights into the WNT-signalling pathway, review its role in the self-renewal of haematopoietic stem cells and in the development of T and B cells, and discuss controversies and future developments with regard to WNT signalling in the thymus.

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Figure 1: Overview of the WNT-signalling pathway.
Figure 2: Important molecules of the WNT-signalling pathway and their sites of interaction.
Figure 3: WNT signalling in haematopoiesis and thymopoiesis.

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Acknowledgements

We thank C. E. van der Linden for careful reading of the manuscript. F.J.T.S. is supported by grants from NWO (The Netherlands), the Fifth and Sixth Framework Programmes (European Union) and the Bekales Foundation (Belgium).

Author information

Authors and Affiliations

  1. Department of Immunology, Room Ee 838, Erasmus Medical Center, Rotterdam, 3015GE, The Netherlands

    Frank J.T. Staal

  2. Hubrecht Laboratory for Developmental Biology, Utrecht, The Netherlands

    Hans C. Clevers

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Correspondence to Frank J.T. Staal.

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DATABASES

Entrez Gene

APC

AXIN

β-catenin

β-TRCP

CK1

DVL

GSK3β

LGS

LRP5

LRP6

PYGO

Tcf1

FURTHER INFORMATION

Frank Staal's laboratory

Hans Clevers's laboratory

Glossary

PRO-B CELLS

Cells at the earliest stage of B-cell development in the bone marrow. They are characterized by incomplete immunoglobulin heavy-chain rearrangement and are defined as CD19+ cytoplasmic IgM− or, sometimes, as B220+ CD43+ (by the Hardy classification scheme).

PRE-B CELLS

(Precursor B cells). Cells at a stage of B-cell development in the bone marrow that are characterized by complete immunoglobulin heavy-chain rearrangement in the absence of immunoglobulin light-chain rearrangement. They express the pre-B-cell receptor, and are phenotypically CD19+ cytoplasmic IgM+ or are sometimes defined as B220+CD43− cell-surface IgM− (by the Hardy classification).

DOUBLE-NEGATIVE SUBSETS

(DN subsets). The most immature thymocytes lack expression of the co-receptors CD4 and CD8, and are referred to as DN cells. This compartment can be further subdivided on the basis of CD25 and CD44 expression into four subpopulations: DN1 (CD25−CD44+), DN2 (CD25+CD44+), DN3 (CD25+CD44−) and DN4 (CD25−CD44−).

IMMATURE SINGLE-POSITIVE POPULATION

(ISP population). Cells at a stage of thymocyte differentiation that occurs between CD4−CD8− double-negative cells and CD4+CD8+ double-positive cells. They are characterized by rapid proliferation and, phenotypically, by the presence of either CD8 (mouse) or CD4 (human), with low levels of CD3 expression (in contrast to the more mature single-positive cells, which are CD3hi).

PLANAR-CELL POLARITY

A morphogenic process in Drosophila melanogaster that orients parallel arrays so that the plane of the epithelium is perpendicular to the apical–basal axis. A homologous process occurs in vertebrates during gastrulation and is sometimes called convergent extension. WNT signalling through JNKs (JUN amino-terminal kinases) is thought to transduce the planar-cell polarity signal.

ADHERENS JUNCTIONS

Specialized intercellular junctions of the plasma membrane, in which the cadherin molecules at the surface of adjacent cells interact in a Ca2+-dependent manner. Actin filaments are linked to these cadherin structures through catenins that are located underneath the junctions.

PROTEASOMAL DEGRADATION

Most of the degradation of cytosolic and nuclear proteins in eukaryotic cells is catalysed by multisubunit proteases known as proteasomes. Targeting of proteins to proteasomes most often occurs through the attachment of multiple ubiquitin tags.

HIGH-MOBILITY-GROUP BOX

(HMG box). A domain present in members of a large protein family that are small non-histone components of chromatin and function in higher-order chromatin structure.

SWI–SNF

An ATP-dependent chromatin-remodelling protein complex that was identified in yeast. Related complexes exist in mammals and are involved in the remodelling of the chromatin of various genes.

MESODERM

In animals with three tissue layers, the mesoderm is the middle layer of tissue, between the ectoderm and the endoderm. In vertebrates, the mesoderm forms the skeleton, muscles, heart, spleen and many other internal organs.

CONDITIONED MEDIUM

Medium collected from culture of a cell line that has been allowed to 'build up' with time so that secreted factors in the medium reach high concentrations. It can be added to cultures of transfected or non-transfected cells, often to provide growth factors and/or cytokines.

IN VIVO COMPLEMENTATION

A method to transfer cells, chromosomes or genes to an organism with a mutant phenotype when the aim is to correct the phenotype. It helps to define a genetic hierarchy between genes and provides an in vivo functional read-out.

NORTHERN BLOTTING

A method for transferring RNA from a denaturing agarose gel to a nitrocellulose filter, on which a particular mRNA can be detected by a suitable DNA probe.

FETAL THYMIC ORGAN CULTURES

(FTOCs). Removal of fetal thymi between embryonic day 14 and 16 allows the analysis of several key processes in thymic development — including antigen-driven positive- and negative-selection events — using in vitro culture. The thymic lobes can also be used to allow the development of progenitor cells that are added to the cultures.

CRE–LOXP

The Cre (cyclization recombinase) protein from bacteriophage P1 excises DNA that is flanked by recombination sequences called loxP sites. These sequences can be introduced at either end of a gene by homologous recombination. Animals carrying LoxP-flanked genes can be made transgenic for the Cre gene, which can be placed under a tissue-specific promoter (for example, Lck for T cells) or an inducible promoter (such as Mx, myxovirus resistance, which is induced by interferon or double-stranded RNA). In the cells that express Cre, the loxP sites are recognized, and the DNA between them is excised, leading to tissue-specific or inducible deletion of the gene of interest.

TRANSLOCATION

Transfer of a segment of a chromosome to a different chromosome, often leading to an abnormal fusion gene or overexpression of one of the genes adjacent to the breakpoint.

BCR–ABL

A tyrosine kinase oncogene. The Abelson leukaemia-virus protein (ABL) is fused with the breakpoint-cluster region (BCR) in the Philadelphia-chromosome translocation found in chronic myeloid leukaemia.

HEMIZYGOUS

A genotype characterized by the presence of both a wild-type and a non-functional allele.

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Staal, F., Clevers, H. WNT signalling and haematopoiesis: a WNT–WNT situation. Nat Rev Immunol 5, 21–30 (2005). https://doi.org/10.1038/nri1529

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