Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

WNT

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101790

Synonyms

Historical Background

Wnt is a primordial signaling pathway, which is conserved from lower invertebrates to higher vertebrates and mammal (Chen et al. 2008). The founders of this pathway were discovered in the late 1900s in fruit flies and in mouse mammary cancers (Lerner and Ohlsson 2015) The name “Wnt” originated from a combination of wingless (Wg) and integrase1 (Int1). The Int1 gene is an oncogene, while Wg is a developmental gene in drosophila which is homologous to Int1 (Nusse and Varmus 1982; Rijsewijk et al. 1987).

Wnt Proteins Structure

Wnts are secreted glycolipoproteins, which are approximately 350 amino acids long, 40 kDa in molecular weight, and contain several charged cysteine residues (approx. 23–25) (Farin et al. 2016). These cysteine residues mediate Wnt folding and multimerization by regulating the formation of intermolecular and intramolecular disulfide bond (Janda et al. 2012). Wnts have an N-terminal hydrophobic signal sequence, which limits their dispersion and range of biological actions (Takada et al. 2006). The lipids bound to N-terminal of Wnts not only connect them to the cell membrane receptors (Bazan and de Sauvage 2009), but also help to mediate their binding with several other regulatory molecules (for e.g., Wif, sFRP) (Malinauskas et al. 2011). Although Wnts are secreted proteins, they are particularly insoluble and are therefore difficult to be purified. As a consequence, the structure and biochemical properties of Wnts are poorly understood. It has been speculated that Wnt proteins are secreted into the extracellular environment as morphogens (Das et al. 2012).

Function of Wnt Proteins in Development and Disease Pathogenesis

Wnt proteins function as universal factors and constitute a large family of signaling peptides with a diverse role in development that can be found in all clades of metazoans except fungi, plants, and unicellular eukaryotes (Nusse and Varmus 2012). Vertebrates contain a family of 19 Wnt-related genes. Each of these genes has a specific role in the development and is expressed in different cells at different times of maturation (Gavin et al. 1990). Although Wnts have impacted almost every aspect of development i.e. from establishing the polarity of a cell within a tissue to stipulating the complete body axis of an organism, yet there are many mysteries of Wnt that remain obscure. Given the diverse phenotypes produced by Wnt knockouts in mice, it is not surprising that loss of Wnts has dire consequences. Here in we have summarized a few of the functions of these Wnt proteins and the consequences of their knockout phenotypes in Table 1.
WNT, Table 1

List of Wnt proteins and their associated functions in different tissues

Gene

Synonyms

Chromosome

Knockout phenotype

Other functions

References

Wnt1

INT-1

12q13.12

Loss of midbrain and cerebellum

Induces organization isthmus which establishes midbrain/hindbrain boundary and cerebellar territory.

(Nusse and Varmus 1982; McMahon and Bradley 1990; Mastick et al. 1996)

Wnt2

IRP

7q31.2

Placental defects

Promotes cervical carcinoma metastasis

Induces epithelial-mesenchymal transition

Increases dendrite arborization

(Monkley et al. 1996; Wayman et al. 2006; Zhou et al. 2016)

Wnt2B

XWNT2

1p13.2

Short olfactory bulb

Induces gastrulation, neurulation, and cerebral cortex patterning

(Kemp et al. 2005; Tsukiyama and Yamaguchi 2012)

Wnt3

MGC131950, MGC138321, MGC138323

17q21.31-q21.32

Defects in gastrulation, axis formation

Defects in hair growth and structure

Essential for specification of the primitive streak and gastrulation.

Necessary in the epiblast for the maintenance of gastrulation

(Liu et al. 1999; Millar et al. 1999)

Wnt3A

MGC119418

MGC119419

MGC119420

1q42.13

Loss of hippocampus.

Defects in somite and tailbud development

Deficiency in dorsal neural tube derivatives including neural crest cells

Spina bifida

Promotes the proliferation of human ESCs

Induces hematopoietic lineages lymphoid, myeloid, and erythroid

Induces myogenesis by the activation of myogenic differentiation antigen (myoD) expression and skeletal muscle development

(Takada et al. 1994; Greco et al. 1996; Ikeya et al. 1997; Yoshikawa et al. 1997; Yamaguchi et al. 1999b; Petropoulos and Skerjanc 2002; Trowbridge et al. 2010)

Wnt4

WNT-4

1p36.12

Defects in kidney development

Defects in mammary gland morphogenesis

The absence of Mullerian duct and virilization

SERKAL syndrome

Involved in development of kidney, adrenal, pituitary and mammary gland

Regulates the development of female reproductive tract

Important for oocyte development

Maintains female germ cell survival in the fetal ovary

(Stark et al. 1994; Vainio et al. 1999; Brisken et al. 2000; Biason-Lauber et al. 2004; Biason-Lauber and Konrad 2008; Mandel et al. 2008; Liu et al. 2010)

Wnt5A

hWNT5a

3p14.3

Shortened anterior-posterior axis with truncated limbs, genitals, and tails

Reduced number of proliferating cells

Cardiac deformities

Imperforate anus

Regulates cell fate in hair follicles

Induces neuronal growth and axonal guidance by activating intracellular calcium release

Regulates hematopoietic stem cell proliferation.

Participates in lung, cardiac, and intestine morphogenesis

Required for cardiac outflow tract septation in mice

(Yamaguchi et al. 1999a; Lickert et al. 2001; Li et al. 2002; Schleiffarth et al. 2007; Cohen et al. 2008; Cervantes et al. 2009; Li et al. 2009; Hu et al. 2010; Sinha et al. 2015)

Wnt5B

Wnt-5b

12p13.33

Viable

Promotes adipogenesis by activating PPAR gamma

Regulates mesenchymal cell aggregation and chondrocyte differentiation

(van Tienen et al. 2009; Bradley and Drissi 2011)

Wnt6

-

2q35

Viable

Regulates heart muscle development during organogenesis

Plays an important role in tooth development by promoting human dental papilla differentiation without significant effect on cell proliferation

(Lavery et al. 2008; Wang et al. 2010)

Wnt7A

-

3p25.1

Defects in limb polarity

Female infertility due to failure of Mullerian duct regression

Defects in synapse maturation in the cerebellum

Defects in uterine patterning

Regulates terminal differentiation of cerebellar granule neurons.

Induces remodeling of axons and growth cones of mossy fiber afferents during the formation of synaptic connections with granule neuron dendrites

(Parr and McMahon 1995; Miller and Sassoon 1998; Parr et al. 1998; Hall et al. 2000)

Wnt7B

-

22q13.31

Placental defects

Perinatal death due to respiratory failure

Regulates medullary capillary development

(Parr et al. 2001; Roker et al. 2016)

Wnt8A

WNT8D

5q31.2

Viable

Formation and patterning of inner ear

Regulates vertebrate mesoderm development

Cooperate with Wnt 3a to promote mammalian body extension

(Narayanan et al. 2011; Vendrell et al. 2013; Cunningham et al. 2015)

Wnt8B

-

10q24.31

Viable

Patterning of dorsal telencephalon

(Hasenpusch-Theil et al. 2015)

Wnt9A

WNT14A

1q42.13

Skeletal abnormalities and synovial chondroid metaplasia

Promotes cell proliferation in the Atrioventricular (AV) anal

(Person et al. 2005; Spater et al. 2006)

Wnt9B

WNT14B, WNT15

17q21.32

Defects in urogenital development (vestigial kidneys and absence of reproductive duct)

Mayer-Rokitansky-Küster-Hauser syndrome

Plays important role in retinal development

Regulates progenitor cell expansion and differentiation during kidney development

Regulates upper jaw and lip development

(Carroll et al. 2005; Karner et al. 2011; Jin et al. 2012; Waschk et al. 2016)

Wnt10B

WNT-12, SHFM6

12q13.12

Inhibition of adipogenesis

Accelerated myogenic differentiation of myoblasts and increased activation of adipogenic genes upon muscle regeneration

(Ross et al. 2000; Vertino et al. 2005)

Wnt11

HWnt family member 11

11q13.5

Kidney tubular abnormalities and secondary glomerular cystogenesis

Controls ventricular myocardium development

(Nagy et al. 2010; Nagy et al. 2016)

Wnt16

-

7q31.31

Viable

Regulation of periosteal bone formation and cortical bone thickness

(Gori et al. 2015; Wergedal et al. 2015)

Conclusion

Wnt signaling pathway plays an essential role in regulating a diverse range of cellular functions. However, the aberrant activation of Wnt signaling has been associated with cancerous transformation in numerous tissues such as breast, liver, colon, and others. In the present review, we have traced the emerging role of Wnts as a critical regulator in the maintenance of homeostasis and regeneration of different mammalian tissues. Further we have also briefly discussed how misregulation of Wnt pathways leads to developmental anomalies.

Future Challenges and Perspectives

Owing to the importance of the Wnt signaling in a wide range of biological fields, a better understanding of the precise mechanism of Wnt signaling might provide fundamental insights regarding its role in disease development and may also provide novel targets for therapeutic interventions. Past few decades have seen a prompt extension in the understanding of regulatory circuitry and complexity of Wnt pathway, but it is important to remember that we have only begun to uncover the tip of the iceberg when it comes to understanding the role of the Wnt signaling in development and disease. Many of the receptor and ligands combinations remain unexplored. Moreover, despite the urgent need of Wnt signaling-directed drugs, only few drugs have reached early phase of clinical trials. The major challenge for future research is to develop potential drugs against Wnt-dependent cancers, as well as approaches for discovering new ones for repositioning.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment GroupCSIR-Indian Institute of Toxicology ResearchLucknowIndia