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WNT and beta-catenin signalling: diseases and therapies. Nat. Rev. Genet. 5, 691-701 (2004)

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. Wnt signalling pathway. WNT/ β -catenin signalling. WNT/calcium signalling.

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WNT and beta-catenin signalling: diseases and therapies. Nat. Rev. Genet. 5, 691-701 (2004)

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  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 signalling pathway WNT/β-catenin signalling WNT/calcium signalling

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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?

  9. 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

  10. 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

  11. 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

  12. 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

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

  14. Therapeutic modulation of WNT pathways

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

  16. Wnt signalling in the stem cells or progenitors Nature434, 843-850 (2005)

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