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Downregulation of Wnt/β-catenin signaling causes degeneration of hippocampal neurons in vivo

Downregulation of Wnt/β-catenin signaling causes degeneration of hippocampal neurons in vivo. Introduction. Wnt binds to Frizzled or other receptors such as LRP5/6 Downstream signaling cascade including Dvl, GSK-3β, Axin

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Downregulation of Wnt/β-catenin signaling causes degeneration of hippocampal neurons in vivo

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  1. Downregulation of Wnt/β-catenin signaling causes degeneration of hippocampal neurons in vivo

  2. Introduction • Wnt binds to Frizzled or other receptors such as LRP5/6 • Downstream signaling cascade including Dvl, GSK-3β, Axin • Accumulation of β-catenin enters nucleus and forms a complex with Tcf/Lef • This controls the expression of over a 100 genes • Autism, Alzheimer's disease • AD patients with presenilin-1 mutation have low levels of β-catenin • LRP6 variations (influence Tcf/Lef reporter activity) associated with late onset AD

  3. Two strains of transgenic mice: • Control Axin2P-rtTA • Ax2P-rtTA/TRE-Axin-EGFP

  4. Inhibition of Wnt/β-catenin via Tet-On system of Axin expression • DOX to forms a complex with rtTA and binds to the TRE • Turns on both GFP and the gene of interest (Axin) Fig 1 A

  5. Axin∆RGS (RGS domain of Axin deleted) Fig 1 B

  6. Fig 1 C

  7. TDBTN - Total Dendritic branching tip numbers Fig 1D

  8. DMSO - Dissolves ICG-001 and SP600125 • ICG-001 – Inhibitor of Wnt signaling • SP600125 - Inhibitor of JNK Fig 2A

  9. Fig 2B

  10. Fig3A

  11. Fig 3B - C

  12. Fig 4A

  13. Fig 4 B - C

  14. Fig 4D

  15. Fig 5A

  16. Fig 5B - C

  17. Fig 6

  18. Fig 7 A - D

  19. Fig 8 A-B

  20. Fig 8 C

  21. Discussion • Down-regulation of Wnt signaling causes hippocampalneurodegeneration • Ectopically expressed β-catenin and Dvl-1 did not enhance arborization despite previous literature • Yu and Malenka used stabilized form of β-catenin while this study used wild type β-catenin • Rosso tested for Dvl-1 at 2 DIV instead of at 4 and 9 DIVC. • Decreased Wnt signaling may play a part in anxiety responses exhibited in patients with dementia

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