WNT and beta-catenin signalling: WNT and beta-catenin signalling: diseases and therapies. diseases and therapies.

Nat. Rev. Genet. Nat. Rev. Genet. 5, 691-701 (2004)5, 691-701 (2004)

報告同學 : 陳宜芳 組 員 : 陳宜芳 陳彥任 葉儀君 莊健盈 王怡婷 黃冠誠 林佩儒 邱敏熙 楊瑞珠 楊玫琳 曾宜萱 徐袁章

WNT/β-catenin signalling WNT/calcium signalling

Wnt signalling pathwayWnt signalling pathway

A nonsense mutation in Wnt3 causes tetra-amelia---- the loss of all four limbs.

Mutations in Wnt3 are linked to tetra-ameliaMutations in Wnt3 are linked to tetra-amelia

sFRP3 and osteoarthritissFRP3 and osteoarthritis

A SNP is associated with osteoarthritis in females.

This SNP is found in secreted Frizzled-related protein 3 (sFRP3) and reduces the ability of sFRP3 to antagonize Wnt signalling

Wnt signalling might be elevated in osteoarthritis

Chromosomal duplication of Wnt4 and an iChromosomal duplication of Wnt4 and an intersex phenotypentersex phenotype

Wnt4 overexpressionWnt4 overexpression disrupts normal testicular vasculature inhibits testosterone synthesis by repressing steroidogenic factor 1 / β-catenin synergy.

Wnt4 acts as an anti-male factor by interfering Wnt4 acts as an anti-male factor by interfering with with ββ-catenin functions.-catenin functions.

Wnt4 and renal development and diseaseWnt4 and renal development and disease

WNnt4 is a key role in renal tubule formationrenal tubule formation.

A rat model of acute renal failure Wnt4 overexpression

After renal injury CNP (C-type natriuretic peptide) gene expression is activated and correlates with Wnt4 expression.

WNT/β-catenin signalling is involved in polycystic kidney disease (PKD)polycystic kidney disease (PKD)

PKD1 gene mutation

Wnt4 overexpression has been reported in polycystic kidneys in mice.

Wnt5a - a tumor suppressor gene and a Wnt5a - a tumor suppressor gene and a modulator of metastasismodulator of metastasis

Loss of Wnt5a in mammary epithelial cells

phenotypic transformation↑

blocked by overexpression of Wnt5a

Wnt5a signals through Wnt/calcium pathway

suppress cyclin D1 expression

negatively regulate B cell proliferation.

Wnt5a, through its activation of PKC

a highly motile and invasive phenotype.

Wnt1 and the neurodevelopmental hypothWnt1 and the neurodevelopmental hypothesis of schizophreniaesis of schizophrenia

Wnt1 overexpression → altered cell adhesion, synaptic rearrangement and plasticity in the brains of people with schizophrenia.

SNPs in FZ3 are associated with susceptibility to schizophrenia.

Dsh1/Dvl1 -/- mice produces behavioural defects, further linking the Wnt pathway to the modulation of brain activity.

Altered function of Frizzled and LRP5/6Altered function of Frizzled and LRP5/6

• Loss-of-function mutations in FZ4 and LRP5 are linked to familial exudative vitreoretinopathy (FEVR)– a truncated protein that acts in a dominant– negative mann

er

oligomerize with wild-type FZ receptors

trap them in the endoplasmic reticulum

• Whether FZ4 signalling is reduced in FEVR patients?

Altered function of Frizzled and LRP5/6Altered function of Frizzled and LRP5/6

• Activating mutations in LRP5 are linked to high bone mass– an 18-year-old female Nebraska highschool student– An amino-acid change in the extracellular domain of LRP5

linked to this high bone mass phenotype

weak activation of the β-catenin pathway– treatments for osteoporosis?

• Loss-of-function mutations in LRP5 are linked to low bone mass and eye defects

Altered function of cytoplasmic componentsAltered function of cytoplasmic components

Activation of Activation of ββ-catenin signalling and cancer.-catenin signalling and cancer.

AXIN2, familial tooth agenesis and colon cancer.AXIN2, familial tooth agenesis and colon cancer.

• mutations in the tumour suppressor APCAPC

• gain-of-function mutations in the N-terminal

phsphorylation sites

• loss-of-function mutations in AXINAXIN

• non-small-cell lung cancer:

DSH/DVL genes overexpressed

siRNA reduced expression

Am. J. Hum. Genet. 74:1043–1050, 2004

Altered function of cytoplasmic componentsAltered function of cytoplasmic components

Mutations linked to tuberous sclerosis activate Mutations linked to tuberous sclerosis activate ββ-catenin.-catenin.

Activated Activated ββ-catenin signalling in skin.-catenin signalling in skin.

• Tuberous sclerosis complex (TSC) genes Tsc1 or Tsc2

• Proteins encoded from TSC genes from complexes and

reduce the level of β-catenin

• TSC complex co-immunoprecipitates with AXIN and

GSK3

Development, 130: 2793, 2003

Altered function of cytoplasmic componentsAltered function of cytoplasmic componentsActivated Activated ββ-catenin signalling in pulmonary fibrosis-catenin signalling in pulmonary fibrosis

Attenuated Attenuated ββ-catenin signaling in Alzheimer disease-catenin signaling in Alzheimer disease

AJP 162: 1393, 2003

TRENDS in Pharmacological Sciences 24: 233, 2003

Altered function of cytoplasmic components

Cardiovascular diseaseCardiovascular disease

PNAS, 100: 5834, 2003

Therapeutic modulation of WNT pathwaysTherapeutic modulation of WNT pathways

Wnt/Wnt/ββ-catenin in the morphogenesis of c-catenin in the morphogenesis of chicken liver hicken liver

Dev. Biol. 266, 109−122

Wnt signalling in the stem cells or progenitors Wnt signalling in the stem cells or progenitors

Nature 434, 843-850 (2005)