WNT and beta-catenin signalling: diseases and therapies. Nat. Rev Download

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WNT and beta-catenin signalling:
diseases and therapies.
Nat. Rev. Genet. 5, 691-701 (2004)
報告同學: 陳宜芳
組
員: 陳宜芳 陳彥任
莊健盈 王怡婷
林佩儒 邱敏熙
楊玫琳 曾宜萱
葉儀君
黃冠誠
楊瑞珠
徐袁章
Wnt signalling pathway
WNT/-catenin signalling
WNT/calcium signalling
Mutations in Wnt3 are linked to tetra-amelia
A nonsense mutation in Wnt3 causes tetra-amelia---- the loss of all
four limbs.
sFRP3 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
intersex phenotype
Wnt4 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
with β-catenin functions.
Wnt4 and renal development and disease
WNnt4 is a key role in renal 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)
 PKD1 gene mutation
 Wnt4 overexpression has been reported in polycystic kidneys in mice.
Wnt5a - a tumor suppressor gene and a
modulator 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
hypothesis 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 LRP5/6
• Loss-of-function mutations in FZ4 and LRP5 are
linked to familial exudative vitreoretinopathy
(FEVR)
– a truncated protein that acts in a dominant– negative
manner
 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 LRP5/6
• 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 components
Activation of b-catenin signalling and cancer.
• mutations in the tumour suppressor APC
• gain-of-function mutations in the N-terminal
phsphorylation sites
• loss-of-function mutations in AXIN
• non-small-cell lung cancer:
DSH/DVL genes overexpressed
siRNA reduced expression
AXIN2, familial tooth agenesis and colon cancer.
Am. J. Hum. Genet. 74:1043–1050, 2004
Altered function of cytoplasmic components
Mutations linked to tuberous sclerosis activate b-catenin.
• Tuberous sclerosis complex (TSC) genes Tsc1 or Tsc2
• Proteins encoded from TSC genes from complexes and
reduce the level of b-catenin
• TSC complex co-immunoprecipitates with AXIN and
GSK3
Activated b-catenin signalling in skin.
Development, 130: 2793, 2003
Altered function of cytoplasmic components
Activated b-catenin signalling in pulmonary fibrosis
AJP 162: 1393, 2003
Attenuated b-catenin signaling in Alzheimer disease
TRENDS in Pharmacological Sciences 24: 233, 2003
Altered function of cytoplasmic components
Cardiovascular disease
PNAS, 100: 5834, 2003
Therapeutic modulation of WNT pathways
Wnt/b-catenin in the morphogenesis of
chicken liver
Dev. Biol. 266, 109−122
Wnt signalling in the stem cells or progenitors
Nature 434, 843-850 (2005)