Role of the Wnt receptor Frizzled-1 in presynaptic differentiation and function.
BACKGROUND
The Wnt signaling pathway regulates several fundamental developmental processes and recently has been shown to be involved in different aspects of synaptic differentiation and plasticity. Some Wnt signaling components are localized at central synapses, and it is thus possible that this pathway could be activated at the synapse.


RESULTS
We examined the distribution of the Wnt receptor Frizzled-1 in cultured hippocampal neurons and determined that this receptor is located at synaptic contacts co-localizing with presynaptic proteins. Frizzled-1 was found in functional synapses detected with FM1-43 staining and in synaptic terminals from adult rat brain. Interestingly, overexpression of Frizzled-1 increased the number of clusters of Bassoon, a component of the active zone, while treatment with the extracellular cysteine-rich domain (CRD) of Frizzled-1 decreased Bassoon clustering, suggesting a role for this receptor in presynaptic differentiation. Consistent with this, treatment with the Frizzled-1 ligand Wnt-3a induced presynaptic protein clustering and increased functional presynaptic recycling sites, and these effects were prevented by co-treatment with the CRD of Frizzled-1. Moreover, in synaptically mature neurons Wnt-3a was able to modulate the kinetics of neurotransmitter release.


CONCLUSIONS
Our results indicate that the activation of the Wnt pathway through Frizzled-1 occurs at the presynaptic level, and suggest that the synaptic effects of the Wnt signaling pathway could be modulated by local activation through synaptic Frizzled receptors.
Varela-Nallar
Lorena
L
Centro de Envejecimiento y Regeneración, Centro de Regulación Celular y Patología Joaquín V Luco and MIFAB, Chile. lpvarela@uc.cl
Grabowski
Catalina P
CP
Alfaro
Iván E
IE
Alvarez
Alejandra R
AR
Inestrosa
Nibaldo C
NC
D000375:Aging; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D051157:Frizzled Receptors / Q000378:metabolism*; D006624:Hippocampus / Q000254:growth & development / Q000502:physiology*; D007700:Kinetics; D009474:Neurons / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D017729:Presynaptic Terminals / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D015398:Signal Transduction; D013569:Synapses / Q000502:physiology; D013572:Synaptic Vesicles / Q000502:physiology; D013574:Synaptosomes / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein
D051157:Frizzled Receptors; D018377:Neurotransmitter Agents; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter; D051153:Wnt Proteins; D060508:Wnt3 Protein; C078603:Fzd1 protein, rat