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

April 1, 2011

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

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

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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

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Axin∆RGS (RGS domain of Axin deleted)

Fig 1 B

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Fig 1 C

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Fig 1D

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 Fig 2A

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Fig 2B

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Fig3A

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Fig 3B - C

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Fig 4A

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Fig 4 B - C

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Fig 4D

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Fig 5A

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Fig 5B - C

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Fig 6

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Fig 7 A - D

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Fig 8 A-B

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Fig 8 C

Discussion Down-regulation of Wnt signaling causes

hippocampal neurodegeneration 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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