1. 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 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

2. WNT/  -catenin signalling WNT/calcium signalling Wnt signalling pathway

4. 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

5. 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.

6. 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.

7. 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.

8. 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.

9. 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?

10. 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

11. 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

12. 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

13. 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

14. Altered function of cytoplasmic components Cardiovascular disease PNAS, 100: 5834, 2003

15. Therapeutic modulation of WNT pathways

16. Wnt/  -catenin in the morphogenesis of chicken liver Dev. Biol. 266, 109−122

17. Wnt signalling in the stem cells or progenitors Nature 434, 843-850 (2005)