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Wnt signaling pathway diagram

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updated June 2010

The Wnt pathway is increasingly becoming more complex and new participants are still being uncovered. It becomes

hard to include all of these new components and the list below is selective. See the simplified map for a further

selection.

Wnt, Porc, Wls/Evi

Wnt genes can be expressed in many different cell types; their expression is not restricted to dedicated cells. There

is control over the secretion and processing of the Wnt protein. Wnt proteins are modified by palmitoylation (Willert

2003) and glycosylation (Mason, 1992). A special form of monounsaturated palmitoylation has been detected on a

serine residue in the Wnt protein (Takada 2006)

The Porcupine (Porc) protein may be involved in secretion or ER transport, as Wingless is retained in the ER in

porcupinemutant Drosophila embryos (Kadowaki 1996, van den Heuvel 1993). In C. elegans, the porcupine

homolog mom-1has a similar function in promoting secretion of the Wnt protein Mom-2 (Rocheleau 1997).

Porcupine has some homology to a family of o-acyl transferases and may be involved in lipid modification of Wnt

proteins (Hofmann, 2000, Willert 2003, Zhai, 2004, Takada 2006). In addition to porcupine, several other proteins,

including the transmembrane Wls/Evi are specifically involved in Wnt secretion (Banziger, 2006; Bartscherer,

2006).Even though there is control over Wnt secretion, there is no evidence that the function of genes like porcupine

and Wls/Evi is restricted to particular cells implying that once Wnt genes are expressed, their proteins will be made

in any cell type.

Frp, WIF, Dkk

In the extracellular space, several secreted proteins can bind directly to Wnts, to modulate Wnt activity.

The secreted Frps (Rattner, 1997) resemble the ligand binding domains of the Frizzled receptor.

WIFs form another group of secreted Wnt binding factors (Hsieh 1999).

Dickkopf (Dkk) in Xenopus antagonizes Wnt action (Glinka1998Fedi, 1999) by binding to LRP (Mao et al,2001,

Bafico et al, 2001; Semenov et al, 2001).

Frizzled, LRP/Arrow, Dsh

Wnts interact genetically and biochemically with a complex of receptors.The specificity between Wnts and receptor

complexes is determined by the Frizzled class of receptors (Bhanot, 1996), of which the CRD (cysteine-rich domain)

is the primary ligand binding domain (Dann et al, 2001).

In Drosophila as well as in vertebrates,LRP (or arrow) is required for Wnt signaling as well, and can bind to Wnt-

Frizzled to form a ternary complex (Wehrli et al, 2000: Tamai et al, 2000; Pinson et al, 2000). The cytoplasmic tail of

LRP can bind to Axin, in a Wnt and phosphorylation dependent manner (Mao et al., 2001, Tolwinsky, 2003, Tamai et

al, 2004). Phosphorylation of the tail of LRP is regulated by two protein kinases: GSK3 and CK1gamma (Zeng,

2005; Davidson 2005; reviewed by Nusse, 2005 . Zeng et al (2008) propose a role for Dsh and Fz in this process as

well. The Wnt signal leads, through its receptor to activation of Dishevelled (Dsh).

Wnt signaling at the level of receptor interactions and activity may be associated with intracellular compartments

such as vacuoles, given the role of the pre-renon receptor as an adaptor between Wnt receptors and the vacuolar

H+-adenosine triphosphatase (V-ATPase) complex (Cruciat, 2010).

beta-catenin , GSK3, Axin, WTX, APC, beta-TrCP

Armadillo/beta-catenin is the key mediator of the Wnt signal.

In cells not exposed to the signal, beta-catenin levels are kept low through interactions with the protein kinase GSK-

3b, CK1a, APC and Axin (Behrens, 1998 Itoh 1998.,Hamada, 1999.) Another player in this complex is the Wilms

tumor suppressor gene WTX (Major, 2007, Rivera, 2007)

beta-catenin is degraded, after phosphorylation by GSK-3 and CK1 alpha (Yanagawa 2002, Liu 2002, Amit 2002),

through the ubiquitin pathway (Aberle 1997.), involving interactions with beta-TrCP(Jiang 1998, Marikawa 1998,;

reviewed inManiatis 1999)

In a current model, Wnt signaling initially leads to a complex between Dsh, GBP/Frat1, Axin and Zw3/GSK, which

may be the regulatory step in the inactivation of Zw3/GSK (Salic, 2000; Farr 2000). The DIX domain in Axin is similar TCF, Groucho, Brg-1, Lgs, Pygo, Hyx

In the nucleus, in the absence of the Wnt signal,TCFacts as a repressor of Wnt/Wg target genes (Brannon

1997,Bienz 1998 .Riese 1997; also in C. elegans Lin 1998).

TCF can form a complex with Groucho (Cavallo 1998).beta-catenin can convert TCF into a transcriptional activator

of the same genes that are repressed by TCF alone (reviewed in Nusse, 1999). Daniels and Weis (2005) have

shown that beta-catenin displaces Groucho from TCF. Two other key players in this complex are Legless (Bcl9)and

Pygopos (Kramps 2002, Thompson 2002,Parker 2002).

Brg-1 is a mammalian SWI/SNF and Rsc chromatin-remodelling complex protein binding tobeta-catenin and

promoting activity (Barker, 2001)

There are many target genes of the Wnt pathway, listed in a separate table.

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Mouse Wnt genes

Updated December 2009

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There are 19 Wnt genes in the mouse genome.

Most genes linked to MGI, Mouse Genome Informatics. See thecomparative table of all vertebrate Wnt genes

for an explanation of the numbering/nomenclature. There is a separate table for syntenic linkage groups.

Also, see alignments of many Wnt proteins

gene natural allele Phenotype of Knockouts or other functions

Wnt1

(previously called int-1)

swaying

Thomas, 1991

loss midbrain, loss cerebellum McMahon 1990

Thomas KR, 1990, McMahon 1992

deficiency in neural crest derivatives, reduction in

dorsolateral neural precursors in the neural tube

together with Wnt-3A KO Ikeya M, et al.

decrease in the number of thymocytes (with Wnt-4

deletion;Mulroy 2002)

Wnt2

(previously called irp)

placental defects Monkley, 1996

Defective lung development (with Wnt2b; Goss,

2009)

Wnt2b/13

retinal cell differentiation Kubo, 2003, Kubo, 2005

Defective lung development (with Wnt2b; Goss,

2009)

Wnt3 early gastrulation defect; Axis formation (Liu P,

1999; M. Capecchi; personal communication)

Hair growth Kishimoto 2000, Millar 1999

Defect in establishing the AER (Barrow, 2003)

medial-lateral retinotectal topography (Schmitt,

2005)

hippocampal neurogenesis (Lie, 2005)

Wnt3a

vestigial

tail Greco 1996

somites, tailbud defects (Takada, 1994 Greco 1996

Yoshikawa Y, 1997 ) through loss expression

Brachyury (Yamaguchi et al, 1999) This is mediated

by Lef-1 (Galceran, 2001)

deficiency in neural crest derivatives, reduction in

dorsolateral neural precursors in the neural tube

together with Wnt-1 KO Ikeya M, et al.

Loss hippocampus (Lee et al, 2000)

Segmentation oscillation clock (Aulehla 2003)

Left right asymmetry (Nakaya 2005)

HSC self-renewal defect (Luis, 2008)

Wnt4

kidney defects Stark K, 1994, renal vesicle induction

Park, 2007

Sex determination (Kim 2006) defects in female

development; absence Mullerian Duct. Ectopic

Testosterone synthesis in females. Vainio S, et al

1999

side-branching in mammary gland (Brisken, 2000)

decrease in the number of thymocytes (with Wnt-1

deletion; Mulroy 2002)

Repression of the migration of steroidogenic adrenal

precursors into the gonad Jeays-Ward 2003

Anterior-posterior guidance of commissural axons

(not tested in Wnt4 mutant; Lyuksyutova et al,

2003).

Wnt5a truncated limbs, truncated AP axis, reduced number

proliferating cells Yamaguchi 1999

Distal lung morphogenesis (Li, 2002)

Chondrocyte differentiation, longitudinal skeletal

outgrowth (Yang, 2003)

Inhibits B cell proliferation and functions as a tumor

suppressor (Liang 2003)

Defects in posterior growth of the female

reproductuve tract (Mericskay et al, 2004)

shortened and widened cochlea (planar polarity)

Qian 2007

Mammary gland phenotype (Roarty, 2007)

prostate gland development Huang 2009

intestinal elongation Cervantes, 2009

endothelial differentiation of ES cells Yang, 2009

Wnt5b

Wnt6

Wnt7a

postaxial

hemimelia

Parr 1998

limb polarity (Parr 1995)

female infertility; failure regression of the Mullerian

duct because the receptor for Mullerian-inhibiting

substance is not expressed.Parr 1998

maintenance appropriate uterine patterning during

the development of the mouse female reproductive

tract (Miller 1998)

Delayed maturation synapses in Cerebellum (Hall,

2000)

High levels cell death in response to DES in the

Female Reproductive Tract (Carta L, Sassoon D,

2004)

May promote neuronal differentiation (Hirabayashi

2004)

CNS vasculature (with Wnt7b, Stenman 2008)

Wnt7b

Placental developmental defects (Parr, 2001)

Respiratory failure; defects in early mesenchymal

proliferation leading to lung hypoplasia (Shu, 2002)

macrophage-induced programmed cell death

(Lobov, 2005) also in LRP5 and LEF1 mutants)

Lung development (Rajagopal 2008)

CNS vasculature (with Wnt7a, Stenman 2008,

Liebner 2008)

cortico-medullary axis in the kidney (Yu et al, 2009)

Wnt8a

Wnt8b  Loss of function mutant: no effect on neural

development, but changes in gene expression.

(Fotaki, 2009)

Wnt9a

(prev. Wnt14)

Loss of function mutant: Joint integrity (Spater 2006)

Wnt9b

(prev. Wnt15)

regulation of mesenchymal to epithelial transitions

(Carroll, 2005)

renal vesicle induction Park, 2007

planar cell polarity of the kidney epithelium (Karner,

2009)

Wnt10a

Wnt10b

Taste Papilla Development (Iwatsuki, 2007)

Loss of function mutant: decreased trabecular bone

(Bennett 2005)

Loss gene promotes Coexpression of Myogenic and

Adipogenic program (Vertino, 2005)

Overexpression inhibits adipogenesis Ross, 2000

Wnt11

Ureteric branching defects (Majumdar, 2003) Kispert

A 1996

Cardiogenesis Pandur 2002

Wnt16Activated by E2A-Pbx1 fusion protein in Pre-B ALL

McWhirter 1999

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Vertebrate Wnt genes

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Comparative table of all vertebrate Wnt genes (upd. April , 2003)

In the following table, the red diamond ♦ indicates that the particular Wnt gene has been

identified.

There are additional tables for each species and a separate table for syntenic linkage

groups for mouse and human genes. See the footnotes for more info.

See alignments Wnts

Wnt genes in Vertebrates

gene Mouse Human Xenopus Chicken Zebrafish

Wnt1 ♦ ♦ ♦ ♦ ♦

Wnt2 ♦ ♦ ♦ ♦

Wnt2B ♦ ♦ ♦ ♦

Wnt3 ♦ ♦ ♦ ♦

Wnt3A ♦ ♦ ♦ ♦

Wnt4 ♦ ♦ ♦ ♦ ♦

Wnt4B ♦

Wnt5A ♦ ♦ ♦ ♦ ♦

Wnt5B ♦ ♦ ♦

Wnt6 ♦ ♦ ♦

Wnt7A ♦ ♦ ♦ ♦ ♦

Wnt7B ♦ ♦ ♦ ♦

Wnt7C ♦

gene Mouse Human Xenopus Chicken Zebrafish

Wnt8A ♦ ♦ ♦ ♦ ♦

Wnt8B ♦ ♦ ♦ ♦ ♦

Wnt9A ♦ ♦ ♦

Wnt9B ♦ ♦

Wnt10A ♦ ♦ ♦ ♦

Wnt10B ♦ ♦ ♦

Wnt11 ♦ ♦ ♦ ♦ ♦

Wnt12, Wnt13, Wnt14, Wnt15 have all been renamed, see below

Wnt-16 ♦ ♦

notes

1. A gene called Wnt-12 identified by Adamson et al is the same as reported by Lee et al, Hardiman et al, and Wang

and Shackleford; and called Wnt-10B. As this mouse Wnt gene is indeed very similar to Wnt-10 genes cloned from

Xenopus and Zebrafish (Wolda, S. L. and Moon, R. T. (1992) and it should be called Wnt-10B.

2. The gene called human Wnt-13 (Katoh et al, 1996) is very similar to the human Wnt-2 and is better named Wnt-2B.

The first Wnt-2 cloned from Xenopus is called XWnt-2 Wolda, S. L. and Moon, R. T. (1992) but it is the ortholog of

Wnt-2B/Wnt13. A Xenopus Wnt-2 cloned by Landesman Y and Sokol SY (1997) is called XWnt-2B, but is actually the

ortholog of the human and mouse Wnt-2.

3. The chicken Wnt-8C is probably the true ortholog of Xenopus Wnt-8A, as these genes are very similar. In addition,

there are no other chicken Wnt-8 genes yet, nor have separate orthologs of CWnt-8C been cloned from the mouse

and the human.

4. Wnt9 was initially only isolated from Hagfisch (Eptatretus stouti) and Thresher Shark (Alopius vulpinus) Sidow

1992. It was realized byQian et al (2003) that the genes first called Wnt14 and Wnt15 are orthologs of Wnt9. Wnt14

and Wnt15 have therefore been renamed into Wnt9A and Wnt9B.

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Human Wnt genes (updated, links restored October 2009)

Note: there are 19 human Wnt genes altogether

There is a separate table for syntenic linkage groups. See the comparative table of all vertebrate Wnt genes for and explanation of the numbering/nomenclature. Also, see alignments of Wnt proteins

Linked to HUGO Disease

WNT1

WNT2

WNT2B/13

WNT3Tetra-Amelia (Niemann 2004)

WNT3A

WNT4 Mullerian-duct regression and virilization (Biason-Lauber 2004)

SERKAL syndrome (Mandel, 2008)

WNT5A

WNT5B

Associated with Susceptibility to type 2 diabetes (Kanazawa 2004)

WNT6

WNT7AFuhrmann syndrome

WNT7B

WNT8A

WNT8B

WNT9A

(previously WNT14)

WNT9B

Previously WNT15)

WNT10A

Odonto-onycho-dermal dysplasia Adaimy, 2007 , Bohring, 2009

WNT10B

 Mutations in Obesity patients Christodoulides 2006

Split-Hand/Foot Malformation (Ugur 2008)

WNT11

WNT16