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SUMMARY:Deconstructing synapses with Wnt antagonists - Patricia C. Salinas
   Department of Cell and Developmental Biology\, University College London
 . London WC1 6BT. UK.
DTSTART:20090331T155500Z
DTEND:20090331T164000Z
UID:TALK17645@talks.cam.ac.uk
CONTACT:Anna Di Pietro
DESCRIPTION:Synapses are highly dynamic structures that are formed\, remod
 elled and eliminated throughout life. Following the initial peak of postna
 tal synaptogenesis these events determine and sculpt functional neural cir
 cuits. Whilst emerging evidence is unravelling many of the key molecules i
 nvolved mechanistic details are still missing.\nWe have previously demonst
 rated that secreted Wnts act as target-derived signals that regulate termi
 nal arborisation of axons and presynaptic assembly. \nLoss of function stu
 dies using Wnt deficient mice combined with gain of function approaches sh
 owed that Wnt signalling regulates synapse formation by inducing the recru
 itment of synaptic components to future synaptic sites. Moreover\, the use
  of the secreted Wnt antagonists like Frizzled related proteins (Sfrps) ha
 s allowed us to demonstrate by cellular and electrophysiological approache
 s that Wnt7a signalling regulates the formation of excitatory synapses in 
 the hippocampus.  \nThe pattern of expression of Wnts\, their receptors an
 d many of the components of the canonical Wnt signalling pathway suggest t
 hat Wnts do not only regulate synapse formation but also synaptic maintena
 nce. To further examine the mechanism of Wnt action at synapses\, we have 
 tested the contribution of the canonical Wnt signalling pathway that requi
 res the co-receptor LRP6\, Dishevelled and inhibition Gsk3ß\, a serine/th
 reonine kinase. We used the Wnt antagonist Dickopf-1 (Dkk1)\, which direct
 ly binds to the LRP6 receptor\, exclusively blocks canonical signalling. I
 n inducible transgenic mice\, expression of Dkk1 in the adult hippocampus 
 decreases the level of presynaptic markers suggesting Wnt signaling is req
 uired for synaptic maintenance. In cultured hippocampal neurons\, Dkk1 blo
 cks Wnt-mediated presynaptic differentiation in hippocampal neurons. Dkk1 
 can also reduce the number of functional synaptic sites in the absence of 
 exogenous Wnt. Intriguingly Dkk1 rapidly reduces (within 30 minutes) the n
 umber of presynaptic sites and the co-localisation of presynaptic proteins
  in a transcriptional independent manner. We also found ultrastructural co
 rrelates for synaptic disassembly and shrinking. Our data strongly suggest
  that canonical-Wnts regulate both the formation and maintenance of synaps
 es in the central nervous system. \n\n
LOCATION:Cripps Court\, Magdalene College
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