WNT and beta-catenin signalling: diseases and therapies. Nat. Rev. Genet. 5, (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/ -catenin signalling WNT/calcium signalling Wnt signalling pathway
A nonsense mutation in Wnt3 causes tetra-amelia---- the loss of all four limbs. Mutations in Wnt3 are linked to tetra-amelia 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 renal tubule formation 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. polycystic kidney disease (PKD) 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 -catenin signalling and cancer. AXIN2, familial tooth agenesis and colon cancer. APC mutations in the tumour suppressor APC gain-of-function mutations in the N-terminal phsphorylation sites AXIN loss-of-function mutations in AXIN non-small-cell lung cancer: DSH/DVL genes overexpressed siRNA reduced expression Am. J. Hum. Genet. 74:1043–1050, 2004
Altered function of cytoplasmic components Mutations linked to tuberous sclerosis activate -catenin. Activated -catenin signalling in skin. Tuberous sclerosis complex (TSC) genes Tsc1 or Tsc2 Proteins encoded from TSC genes from complexes and reduce the level of -catenin TSC complex co-immunoprecipitates with AXIN and GSK3 Development, 130: 2793, 2003
Altered function of cytoplasmic components Activated -catenin signalling in pulmonary fibrosis Attenuated -catenin signaling in Alzheimer disease AJP 162: 1393, 2003 TRENDS in Pharmacological Sciences 24: 233, 2003
Altered function of cytoplasmic components Cardiovascular disease PNAS, 100: 5834, 2003
Therapeutic modulation of WNT pathways
Wnt/ -catenin in the morphogenesis of chicken liver Dev. Biol. 266, 109−122
Wnt signalling in the stem cells or progenitors Nature 434, (2005)