Downregulation of Wnt/

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

• Wnt binds to Frizzled or other receptors such as
  LRP5/6
• Downstream signaling cascade including Dvl,
  GSK-3ß, Axin
• Accumulation of ß-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 ß-catenin
• LRP6 variations (influence Tcf/Lef reporter
  activity) associated with late onset AD

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

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• Inhibition of Wnt/ß-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)

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• Axin?RGS (RGS domain of Axin deleted)

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TDBTN - Total Dendritic branching tip numbers
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• DMSO - Dissolves ICG-001 and SP600125
• ICG-001 Inhibitor of Wnt signaling
• SP600125 - Inhibitor of JNK

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Discussion

• Down-regulation of Wnt signaling causes
  hippocampal neurodegeneration
• Ectopically expressed ß-catenin and Dvl-1 did not
  enhance arborization despite previous literature
• Yu and Malenka used stabilized form of ß-catenin
  while this study used wild type ß-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